Pectinesterase (pectin methylesterase) catalyses the de-esterification of pectin into pectate and methanol. Pectin is one of the main components of the plant cell wall. In plants, pectinesterase plays an important role in cell wall metabolism during fruit ripening. In plant bacterial pathogens such as Erwinia carotovora and in fungal pathogens such as Aspergillus niger, pectinesterase is involved in maceration and soft-rotting of plant tissue. Plant pectinesterases are regulated by pectinesterase inhibitors, which are ineffective against microbial enzymes [].Prokaryotic and eukaryotic pectinesterases share a few regions of sequence similarity. The crystal structure of pectinesterase from Erwinia chrysanthemi revealed a β-helix structure similar to that found in pectinolytic enzymes, though it is different from most structures of esterases []. The putative catalytic residues are in a similar location to those of the active site and substrate-binding cleft of pectate lyase.The entry represents a region found in the N-terminal section of these enzymes; it contains a conserved tyrosine which may play a role in the catalytic mechanism [].
Lyn is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lyn is expressed in B lymphocytes and myeloid cells. It exhibits both positive and negative regulatory roles in B cell receptor (BCR) signaling. Lyn, as well as Fyn and Blk, promotes B cell activation by phosphorylating ITAMs (immunoreceptor tyr activation motifs) in CD19 and in Ig components of BCR []. It negatively regulates signaling by its unique ability to phosphorylate ITIMs (immunoreceptor tyr inhibition motifs) in cell surface receptors like CD22 and CD5 []. Lyn also plays an important role in G-CSF receptor signaling by phosphorylating a variety of adaptor molecules []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Dual specificity protein phosphatases mediate dephosphorylation of proteins phosphorylated on Tyr and Ser/Thr residues. Dual specificity phosphatase 23 can dephosphorylate p44-ERK1 (MAPK3) but not p54 SAPK-beta (MAPK10) in vitro. It is able to enhance activation of JNK and p38 (MAPK14) [].
This family of proteins is functionally uncharacterised. This family of proteins is found in bacteria, mainly in Firmicutes. Proteins in this family are typically between 454 and 596 amino acids in length. There are two highly conserved residues, a Tyr and an Asp.
This family of proteins is functionally uncharacterised. This family of proteins is found in bacteria. Proteins in this family are typically between 151 and 172 amino acids in length. This family has a conserved sequence motif DER and two conserved residues, a Tyr and a Gly.
This family of proteins is functionally uncharacterised. This family of proteins is mainly found in firmicutes. Proteins in this family are approximately 170 amino acids in length. There are two conserved motifs, CxxF and YxN, and two conserved residues, Tyr at the N-terminal and a Gly at the C-terminal. Many members of this family are thought to belong to the Thioredoxin superfamily.
TXK is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal cysteine-rich region. TXK forms a complex with EF-1alpha and PARP1 that regulates interferon-gamma gene transcription in Th1 cells []. This entry represents the SH3 domain of TXK.
Lck is a member of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Lck is expressed in T-cellsand natural killer cells. It plays a critical role in T-cell maturation, activation, and T-cell receptor (TCR) signaling [, ]. Lck phosphorylates ITAM (immunoreceptor tyr activation motif) sequences on several subunits of TCRs, leading to the activation of different second messenger cascades. Phosphorylated ITAMs serve as binding sites for other signaling factor such as Syk and ZAP-70, leading to their activation and propagation of downstream events []. In addition, Lck regulates drug-induced apoptosis by interfering with the mitochondrial death pathway. The apototic role of Lck is independent of its primary function in T-cell signaling []. Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
Fyn and Yrk (Yes-related kinase) are members of the Src subfamily of proteins, which are cytoplasmic (or non-receptor) PTKs. Fyn, together with Lck, plays a critical role in T-cell signal transduction by phosphorylating ITAM (immunoreceptor tyr activation motif) sequences on T-cell receptors, ultimately leading to the proliferation and differentiation of T-cells []. In addition, Fyn is involved in the myelination of neurons, and is implicated in Alzheimer's []and Parkinson's diseases []. Yrk has been detected only in chickens. It is primarily found in neuronal and epithelial cells and in macrophages. It may play a role in inflammation and in response to injury [].Src kinases contain an N-terminal SH4 domain with a myristoylation site, followed by SH3 and SH2 domains, a tyr kinase domain, and a regulatory C-terminal region containing a conserved tyr. They are activated by autophosphorylation at the tyr kinase domain, but are negatively regulated by phosphorylation at the C-terminal tyr by Csk (C-terminal Src Kinase). The SH3 domain of Src kinases contributes to substrate recruitment by binding adaptor proteins/substrates, and regulation of kinase activity through an intramolecular interaction [, ].
This entry describes a very small protein, coenzyme PQQ biosynthesis protein A, which is smaller than 25 amino acids in many species. It is proposed to serve as a peptide precursor of coenzyme pyrrolo-quinoline-quinone (PQQ), with Glu and Tyr of a conserved motif Glu-Xxx-Xxx-Xxx-Tyr becoming part of the product [].
This entry represents coenzyme PQQ biosynthesis protein E, which is a prototypical peptide-cyclising radical SAM enzyme. It links a Tyr to a Glu as the first step in the biosynthesis of pyrrolo-quinoline-quinone (coenzyme PQQ) from the precursor peptide PqqA. PQQ is required for some glucose dehydrogenases and alcohol dehydrogenases.This entry also includes some other radical SAM enzymes, such as tungsten-containing aldehyde ferredoxin oxidoreductase cofactor-modifying protein, adoMet-dependent heme synthase []and Fe-coproporphyrin III synthase [].
Receptor tyrosine kinases (RTKs) are transmembrane receptors thathave intrinsic, cytoplasmic tyrosine kinase activity. Juxtamembrane regions in RTKs have been shown to play important regulatory functions. Their kinase activity is generally autoinhibited by its JX domain in the absence of ligand-stimulated tyrosine phosphorylation, due to the inhibitory Tyr phosphorylation sites found in the JX domain []. This superfamily represents the JX domain of the EGF receptor [].
SelO and its homologues are widespread among most eukaryotic taxa, and are also common in many major bacterial taxa. SelO is a conserved pseudokinase that transfers AMP from ATP to Ser, Thr, and Tyr residues on protein substrates (AMPylation). It contains a protein kinase fold with ATP flipped in the active site []. In eukaryotes, it is a mitochondrial protein that may be involved in redox biology [].
BAZ1B (also known as Williams-Beuren syndrome transcription factor, WSTF) is a component of the WICH complex (WSTF-ISWI ATP-dependent chromatin-remodelling complex). It has intrinsic tyrosine kinase activity by means of a domain that shares no sequence homology to any known kinase fold. It has been shown to phosphorylate Tyr 142 of H2A []. It is involved in chromatin assembly, RNA polymerase I and III gene regulation, vitamin D metabolism, and DNA repair [].
Phenylcoumaran benzylic ether reductases and pinoresinol-lariciresinol reductases are NADPH-dependent aromatic alcohol reductases, and are atypical members of the SDR (short-chain dehydrogenase/reductase) family. Other proteins containing this domain are identified as eugenol synthase []. These proteins contain an N-terminal characteristic of NAD(P)-binding proteins and a small C-terminal domain presumed to be involved in substrate binding, but they do not have the conserved active site Tyr residue typically found in SDRs [].
Caspase-14 (MEROPS identifier C14.018) is a cytoplasmic cysteine endopeptidase found only in cornifying tissues such as skin. It is found in epidermal keratinocytes and is involved in a tissue-specific form of senescence, leading to differentiation of keratinocytes to form the cornified cell layer [, ]. Caspase-14 is synthesized as a zymogen, but, unusually for a caspase, activation is not autocatalytic, and cleavage to produce the p20 and p10 subunits occurs in human caspase-14 at Ile152 []. Caspase-14 has a strict requirement for Asp in the P1 position, and positional scanning of substrates shows a preference for hydrophobic residues such as Trp or Tyr in P4 [].
Proteins in this entry contain a fido domain. The domain is named after the Fic and Doc proteins where it is found. Included in this entry are adenosine monophosphate-protein transferase Fic and FICD. Both Fic and FICD add adenosine 5'-monophosphate (AMP) to specific residues of target proteins (AMPylation), or remove the same modification from target proteins (de-AMPylation), depending on whether cells are in a resting state or stressed []. Both bind divalent cations, preferring Mn2+over Mg2+[]. The adenosine monophosphate-protein transferase SoFic from Shewanella oneidensis is known only to add AMP to target proteins, either at Tyr or Thr residues [].
Members of this group combine the LytTR DNA-binding transcriptional regulator domain []with an N-terminal membrane-bound MHYE domain that consists of three predicted transmembrane segments with conserved Glu, Asp, His and Tyr residues. The membrane topology of this domain is somewhat similar to that of MHYT domain [], suggesting that it, too, might be membrane-bound and metal-binding [].A member of this group is RpfD from the plant pathogen Xanthomonas campestris. Although the rpfDgene is located in the rpf(regulation of pathogenicity factors) locus of X. campestris, mutants with transposon insertion in the rpfDgene did not exhibit any discernible phenotype []. The function of this protein is not yet known.
Tyrosine-protein kinase Fgr belongs to the SRC family of the Tyr protein kinases. It is a non-receptor tyrosine-protein kinase that transmits signals from cell surface receptors devoid of kinase activity and contributes to the regulation of immune responses, including neutrophil, monocyte, macrophage and mast cell functions, cytoskeleton remodeling in response to extracellular stimuli, phagocytosis, cell adhesion and migration [, , ]. It contains a protein kinase domain, an SH2 domain and an SH3 domain. Fgr interacts with tyrosine phosphorylated SYK, FLT3 and HCLS1 via its SH2 domain [].This entry represents the SH2 domain of Fgr.
This entry represents the phosphatase domain of Myotubularin-related protein 3 (Mtmf3). Proteins in this entry are specific to chordates. Mtmr3 is a phosphatase that acts on lipids with a phosphoinositol head-group such as phosphatidyl-inositol 3-phosphate and phosphatidyl-inositol 3,5-bisphosphate []. It may also de-phosphorylate proteins phosphorylated on Ser, Thr, and Tyr residues []. This enzyme has shown to play a regulatory role in the regulation of abscission, the final step of mitosis [], and innate immune responses to viral DNA through the modulation of STING trafficking [].
Purple acid phosphatases (PAPs) are ubiquitous binuclear metal-containing acid hydrolases characterised by their acidic pH optima and their intense purple colour due to a TyrO-to-FeIII charge-transfer transition. The amino acid residues coordinating the metal ions are conserved in all PAPs. Active PAPs contain an FeIII ion coordinated to Tyr O, a His N, and an Asp O2, in addition to a divalent metal ion (Fe, Zn, or Mn) coordinated by a His N, a His N, and an Asn O. A hydroxide ion and an Asp O2 bridge the two metal ions []. These enzymes share a high degree of homology within their N-termini [].
NmrA is a negative transcriptional regulator of various fungi, involved in the post-translational modulation of the GATA-type transcription factor AreA []. NmrA lacks the canonical GXXGXXG NAD-binding motif and has altered residues at the catalytic triad, including a Met instead of the critical Tyr residue. NmrA may bind nucleotides but appears to lack any dehydrogenase activity. It lacks most of the active site residues of the SDR (short-chain dehydrogenases/reductases) family, but has an NAD(P)-binding motif similar to the extended SDR family, GXXGXXG [].This domain can also be found in other atypical SDRs, such as HSCARG (an NADPH sensor) []and PCBER (phenylcoumaran benzylic ether reductase) [].
This entry includes proteins of two subfamilies: Ser/Thr () and Tyr dual specificity protein phosphatase and tyrosine specific protein phosphatase (). Both of these subfamilies may also have inactive phosphatase domains, and dependenton the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect against dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided into two classes. Those which bind phosphorylated tyrosine residues may recruit multi-phosphorylated substrates for the adjacent active domains and are more conserved, while the other class have accumulated several variable amino acid substitutions and have a complete loss of tyrosine binding capability. The second class shows a release of evolutionary constraint for the sites around the catalytic centre, which emphasises a difference in function from the first group. There is a region of higher conservation common to both classes, suggesting a regulatory centre [].Ser/Thr and Tyr dual specificity phosphatases are a group of enzymes with both Ser/Thr () and tyrosine specific proteinphosphatase () activity able to remove both the serine/threonine or tyrosine-bound phosphate group from a widerange of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Tyrosine specific protein phosphatases catalyze the removal of a phosphate group attached to a tyrosine residue. They are also very important in the control of cell growth, proliferation, differentiation and transformation.
Chorismate mutase (CM) is a regulatory enzyme () required forbiosynthesis of the aromatic amino acids phenylalanine and tyrosine. CMcatalyzes the Claisen rearrangement of chorismate to prephenate, which cansubsequently be converted to precursors of either L-Phe or L-Tyr. Inbifunctional enzymes the CM domain can be fused to a prephenate dehydratase(P-protein for Phe biosynthesis), to a prephenatedehydrogenase (T-protein, for Tyr biosynthesis), or to3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase.Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur inprokaryotes as well as in fungi, plants and nematode worms []. The sequence of monofunctional chorismate mutase aligns well with the N-terminal part of P-proteins [].The type II or AroQ class of CM has an all-helical 3Dstructure, represented by the CM domain of the bifunctional Escherichia coliP-protein. This type is named after the Enterobacteragglomerans monofunctional CM encoded by the aroQ gene []. All CM domainsfrom bifunctional enzymes as well as most monofunctional CMs belong to thisclass, including archaeal CM.Eukaryotic CM from plants and fungi form a separate subclass of AroQ,represented by the Baker's yeast allosteric CM. These enzymes show onlypartial sequence similarity to the prokaryotic CMs due to insertions ofregulatory domains, but the helix-bundle topology and catalytic residues areconserved and the 3D structure of the E. coli CM dimer resembles a yeast CMmonomer [, , ]. The E. coli P-protein CM domain consists of3 helices and lacks allosteric regulation. The yeast CM has evolved by geneduplication and dimerization and each monomer has 12 helices. Yeast CM isallosterically activated by Trp and inhibited by Tyr [].
Jak2 is widely expressed in many tissues. It is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors []. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities []. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis [, , , ].Jak2 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Despite this, the presumed pseudokinase (repeat 1) domain of Jak2 exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Inactivation of the repeat 1 domain increased Jak2 basal activity, suggesting that it modulates the kinase activity of the C-terminal catalytic (repeat 2) domain [].This entry represents the pseudokinase domain of Jak2.
Jak2 is widely expressed in many tissues. It is essential for the signaling of hormone-like cytokines such as growth hormone, erythropoietin, thrombopoietin, and prolactin, as well as some IFNs and cytokines that signal through the IL-3 and gp130 receptors []. Disruption of Jak2 in mice results in an embryonic lethal phenotype with multiple defects including erythropoietic and cardiac abnormalities []. It is the only Jak gene that results in a lethal phenotype when disrupted in mice. A mutation in the pseudokinase domain of Jak2, V617F, is present in many myeloproliferative diseases, including almost all patients with polycythemia vera, and 50% of patients with essential thrombocytosis and myelofibrosis [, , , ].Jak2 is a cytoplasmic (or nonreceptor) PTK containing an N-terminal FERM domain, followed by a Src homology 2 (SH2) domain, a pseudokinase domain, and a C-terminal tyr kinase domain. The pseudokinase domain shows similarity to tyr kinases but lacks crucial residues for catalytic activity and ATP binding. Despite this, the presumed pseudokinase (repeat 1) domain of Jak2 exhibits dual-specificity kinase activity, phosphorylating two negative regulatory sites in Jak2: Ser523 and Tyr570. Inactivation of the repeat 1 domain increased Jak2 basal activity, suggesting that it modulates the kinase activity of the C-terminal catalytic (repeat 2) domain [].This entry represents the C-terminal catalytic domain.
This entry represents a group of 3-ketodihydrosphingosine reductases, including KDSR from animals and Tsc10 from yeasts and plants. They catalyse the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS) and are required for sphingolipid biosynthesis [, , ].Proteins in this entry show strong conservation of the active site tetrad and glycine rich NAD-binding motif of the classical SDRs. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central β-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing [, , ].Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, 15-PGDH numbering) and/or an Asn (Asn-107, 15-PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction [, , ].
This entry represents the classical-like SDR domain of human WWOX and related proteins. Proteins in this entry share the glycine-rich NAD-binding motif of the classical SDRs, have a partial match to the canonical active site tetrad, but lack the typical active site Ser [, ]. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold (alpha/beta folding pattern with a central β-sheet), an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Classical SDRs are typically about 250 residues long, while extended SDRs are approximately 350 residues. Sequence identity between different SDR enzymes are typically in the 15-30% range, but the enzymes share the Rossmann fold NAD-binding motif and characteristic NAD-binding and catalytic sequence patterns. These enzymes catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG]XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase (15-PGDH) numbering). In addition to the Tyr and Lys, there is often an upstream Ser (Ser-138, 15-PGDH numbering) and/or an Asn (Asn-107, 15-PGDH numbering) contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Extended SDRs have additional elements in the C-terminal region, and typically have a TGXXGXXG cofactor binding motif. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif. Some atypical SDRs have lost catalytic activity and/or have an unusual NAD(P)-binding motif and missing or unusual active site residues. Reactions catalyzed within the SDR family include isomerization, decarboxylation, epimerization, C=N bond reduction, dehydratase activity, dehalogenation, Enoyl-CoA reduction, and carbonyl-alcohol oxidoreduction [, , , ].
Amino acid permeases are integral membrane proteins involved in the transportof amino acids into the cell. A number of such proteins have been found to beevolutionary related [, , ]. Aromatic amino acids are concentrated in the cytoplasm of Escherichia coli by 4 distinct transport systems: a general aromatic amino acid permease, and aspecific permease for each of the 3 types (Phe, Tyr and Trp) []. It has been shown []that some permeases in E. coli and related bacteria are evolutionary related.These permeases are proteins of about 400 to 420 amino acids and are located in the cytoplasmic membrane and, like bacterial sugar/cation transporters, are thought to contain 12 transmembrane (TM)regions []- hydropathy analysis, however, is inconclusive, suggesting thepossibility of 10 to 12 membrane-spanning domains []. The best conserved domain is a stretch of 20 residues which seems to be located in a cytoplasmic loop between thefirst and second transmembrane region.
This entry represents the FF domain of the Rho GTPase activating proteins (GAPs). These are the key proteins that make the switch between the active guanosine-triphosphate-bound form of Rho guanosine triphosphatases (GTPases) and the inactive guanosine-diphosphate-bound form. Rho guanosine triphosphatases (GTPases) are a family of proteins with key roles in the regulation of actin cytoskeleton dynamics.The RhoGAP-FF1 domain have been implicated in binding to the transcription factor TFII-I; and phosphorylation of Tyr308 within the first FF domain inhibits this interaction. The RhoGAP-FF1 domain constitutes the first solved structure of an FF domain that lacks the first of the two highly conserved Phe residues, but the substitution of Phe by Tyr does not affect the domain fold [].
Cyclin-dependent kinases (cdks) are the catalytic subunits of a large family of serine/threonine protein kinases (STKs). They are key regulators of eukaryotic cell cycle progression. CDK10 (also known as PISSLRE) is a cdc2-related kinase that contains the canonical regulatory Tyr and Thr residues present in all protein kinases and a PSTAIRE-like motif named PISSLRE []. CDK10 is essential for cell growth and proliferation, and acts through the G2/M phase of the cell cycle []. CDK10 has also been identified as an important factor in endocrine therapy resistance in breast cancer. CDK10 silencing increases the transcription of c-RAF and the activation of the p42/p44 MAPK pathway, which leads to antiestrogen resistance. Patients who express low levels of CDK10 relapse early on tamoxifen [].
This entry describes GlnD, the uridylyltransferase/uridylyl-removing enzyme for signal-transduction protein PII, and acts as the sensory component of the nitrogen regulation (ntr) system [, ]. The ntr system modulates nitrogen metabolism in response to the prevailing nitrogen source and the requirements of the cell. During nitrogen fixation, ammonia and 2-oxoglutarate can be used to produce glutamate. The activity of the PII protein is stimulated by glutamine and inhibited by 2-oxoglutarate. Under glutamate-limiting conditions, PII is uridylylated by GlnD leading to the activation of glutamate synthetase and to the stimulation of NtrC-dependent promoters. Under high concentrations of fixed nitrogen, PII is de-uridylylated leading to the inactivation of the glutamate synthetase pathway and switching off NtrC-dependent promoters [].Not all homologues of PII share the property of uridylyltransferase modification on the characteristic Tyr residue (see ), but the modification site is preserved in the PII homologue of all species with a member of this family.
Terminase large subunit (TerL) from bacteriophages and evolutionarily related viruses, is an important component of the DNA packing machinery and comprises an ATPase domain, which powers DNA translocation and a nuclease domain that cuts concatemeric DNA [, ]. TerL forms pentamers in which the ATPase domains form a ring distal to the capsid. This is the ATPase domain which contains a C-terminal subdomain that sits above the ATPase active site, called the "Lid subdomain"with reference to analogous lid subdomains found in other ATPases []. It contains a hydrophobic patch (Trp and Tyr residues) that mediates critical interactions in the interface between adjacent ATPase subunits and assists the positioning of the arginine finger residue that catalyses ATP hydrolysis [, ]. This domain is also found in uncharacterised proteins encoded by bacterial prophages, including YmfN from Escherichia coli.
This β-barrel domain is found in FomD, a protein encoded in the fosfomycin biosynthesis gene cluster [, ], which hydrolyzes (S)-HPP-CMP to give (S)-HPP and CMP in the presence of Mn2 or Co2 []. FomD also hydrolyzes cytidylyl 2-hydroxyethylphosphonate (HEP-CMP), which is a biosynthetic intermediate before C-methylation. FomD structure revealed that it has a β-barrel fold consisting of a large twisted antiparallel β-sheet, a key feature of DUF402-containing proteins. The function of this domain is unknown. It has a conserved Tyr residue which activates a water molecule to promote nucleophilic attack on the phosphorus atom of the phosphonate moiety []. This domain has been also found in Ntdp (nucleoside tri- and diphosphatase, also known as Sa1684) from Staphylococcus aureus [].
Aromatic ring hydroxylating dioxygenases are multicomponent 1,2-dioxygenase complexes that convert closed-ring structures to non-aromatic cis-diols []. The complex has both hydroxylase and electron transfer components. The hydroxylase component is itself composed of two subunits: an alpha-subunit of about 50kDa, and a beta-subunit of about 20kDa. The electron transfer component is either composed of two subunits: a ferredoxin and a ferredoxin reductase or by a single bifunctional ferredoxin/reductase subunit. Sequence analysis of hydroxylase subunits of ring hydroxylating systems (including toluene, benzene and napthalene 1,2-dioxygenases) suggests they are derived from a common ancestor []. The alpha-subunit binds both a Rieske-like 2Fe-2S cluster and an iron atom: conserved Cys and His residues in the N-terminal region may provide 2Fe-2S ligands, while conserved His and Tyr residues may coordinate the iron. The beta subunit may be responsible for the substrate specificity of the dioxygenase system [].
Amino acid permeases are integral membrane proteins involved in the transportof amino acids into the cell. A number of such proteins have been found to beevolutionary related [, , ].Aromatic amino acids are concentrated in the cytoplasm of Escherichia coli by 4 distinct transport systems: a general aromatic amino acid permease, and aspecific permease for each of the 3 types (Phe, Tyr and Trp) []. It has been shown []that some permeases in E. coli and related bacteria are evolutionary related.These permeases are proteins of about 400 to 420 amino acids and are located in the cytoplasmic membrane and, like bacterial sugar/cation transporters, are thought to contain 12 transmembrane (TM)regions []- hydropathy analysis, however, is inconclusive, suggesting thepossibility of 10 to 12 membrane-spanning domains []. The best conserved domain is a stretch of 20 residues which seems to be located in a cytoplasmic loop between thefirst and second transmembrane region.This entry represents a conserved site specific for tyryptophan and tyrosine permeases.
This entry represents the SH3 domain of Tec [, ]. Tec is a cytoplasmic (or nonreceptor) tyrosine kinase containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain []. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions []. It is more widely-expressed than other Tec subfamily kinases. Tec is found in endothelial cells, both B- and T-cells, and a variety of myeloid cells including mast cells, erythroid cells, platelets, macrophages and neutrophils [, ]. Tec is a key component of T-cell receptor (TCR) signaling, and is important in TCR-stimulated proliferation and phospholipase C-gamma1 activation [].
This β-barrel domain is found in FomD, a protein encoded in the fosfomycin biosynthesis gene cluster [, ], which hydrolyzes (S)-HPP-CMP to give (S)-HPP and CMP in the presence of Mn2 or Co2 []. FomD also hydrolyzes cytidylyl 2-hydroxyethylphosphonate (HEP-CMP), which is a biosynthetic intermediate before C-methylation. FomD structure revealed that it has a β-barrel fold consisting of a large twisted antiparallel β-sheet, a key feature of DUF402-containing proteins. The function of this domain is unknown. It has a conserved Tyr residue which activates a water molecule to promote nucleophilic attack on the phosphorus atom of the phosphonate moiety []. This domain has been also found in Ntdp (nucleoside tri- and diphosphatase, also known as Sa1684) from Staphylococcus aureus [].
This domain represents a region comprised between residues 522 and 583 from fission yeast protein Atg11 (also known as Taz1-interacting factor 1). This domain is necessary and sufficient for Atg11 autophagy function and for supporting Atg1 kinase activity as it harbours an Atg1-binding domain at the N terminus and a homodimerization domain at the C terminus. The N-terminal part of this domain contains the conserved aromatic residues Phe and Tyr necessary for the direct and specific interaction with the tMIT domain of Atg1. This interaction is required for the autophagy function of Atg11. The C-terminal part of this domain, residues 546-583, is predicted to adopt a coiled-coil conformation which mediates Atg11 homodimerization []. Proteins containing this domain seem to be restricted to Schizosaccharomyces.
Purple acid phosphatases (PAPs) are ubiquitous binuclear metal-containing acid hydrolases characterised by their acidic pH optima and their intense purple colour due to a TyrO-to-FeIII charge-transfer transition. The amino acid residues coordinating the metal ions are conserved in all PAPs. Active PAPs contain an FeIII ion coordinated to Tyr O, a His N, and an Asp O2, in addition to a divalent metal ion (Fe, Zn, or Mn) coordinated by a His N, a His N, and an Asn O. A hydroxide ion and an Asp O2bridge the two metal ions []. These enzymes share a high degree of homology within their N-termini [].This entry also includes phospholipase D, the structure of which has been solved from Bacillus subtilis and shows a purple acid phosphatase-like fold [].
Chorismate mutase (CM) is a regulatory enzyme () required forbiosynthesis of the aromatic amino acids phenylalanine and tyrosine. CMcatalyzes the Claisen rearrangement of chorismate to prephenate, which cansubsequently be converted to precursors of either L-Phe or L-Tyr. Inbifunctional enzymes the CM domain can be fused to a prephenate dehydratase(P-protein for Phe biosynthesis), to a prephenatedehydrogenase (T-protein, for Tyr biosynthesis), or to3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase.Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur inprokaryotes as well as in fungi, plants and nematode worms []. The sequence of monofunctional chorismate mutase aligns well with the N-terminal part of P-proteins [].The type II or AroQ class of CM has an all-helical 3Dstructure, represented by the CM domain of the bifunctional Escherichia coliP-protein. This type is named after the Enterobacteragglomerans monofunctional CM encoded by the aroQ gene []. All CM domainsfrom bifunctional enzymes as well as most monofunctional CMs belong to thisclass, including archaeal CM.Eukaryotic CM from plants and fungi form a separate subclass of AroQ,represented by the Baker's yeast allosteric CM. These enzymes show onlypartial sequence similarity to the prokaryotic CMs due to insertions ofregulatory domains, but the helix-bundle topology and catalytic residues areconserved and the 3D structure of the E. coli CM dimer resembles a yeast CMmonomer [, , ]. The E. coli P-protein CM domain consists of3 helices and lacks allosteric regulation. The yeast CM has evolved by geneduplication and dimerization and each monomer has 12 helices. Yeast CM isallosterically activated by Trp and inhibited by Tyr [].This entry represents the CM type 2 domain, mainly from prokaryotes. It does not include the CM from plants and or Baker's yeast.
Chorismate mutase (CM) is a regulatory enzyme () required for biosynthesis of the aromatic amino acids phenylalanine and tyrosine. CM catalyzes the Claisen rearrangement of chorismate to prephenate, which can subsequently be converted to precursors of either L-Phe or L-Tyr. In bifunctional enzymes the CM domain can be fused to a prephenate dehydratase (P-protein for Phe biosynthesis), to a prephenate dehydrogenase (T-protein, for Tyr biosynthesis), or to 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase (). Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur in prokaryotes as well as in fungi, plants and nematode worms [].The type I or AroH class of CM is represented by Bacillus subtilis aroH, a monofunctional, nonallosteric, homotrimeric enzyme characterized by its pseudo-alpha/β-barrel 3D structure. Each monomer folds into a 5-stranded mixed β-sheet packed against an α-helix and a 3-10 helix. The core is formed by a closed barrel of mixed β-sheets surrounded by helices. The interfaces between adjacent subunits form three equivalent clefts that harbor the active sites [].The type II or AroQ class of CM has a completely different all-helical 3D structure, represented by the CM domain of the bifunctional Escherichia coli P-protein. This type is named after the Enterobacter agglomerans monofunctional CM encoded by the aroQ gene []. All CM domains from bifunctional enzymes as well as most monofunctional CMs belong to this class, including archaeal CM.Eukaryotic CM from plants and fungi form a separate subclass of AroQ, represented by the Baker's yeast allosteric CM []. These enzymes show only partial sequence similarity to the prokaryotic CMs due to insertions of regulatory domains, but the helix-bundle topology and catalytic residues are conserved and the 3D structure of the E. coli CM dimer resembles a yeast CM monomer [, , ]. The E. coli P-protein CM domain consists of 3 helices and lacks allosteric regulation. The yeast CM has evolved by gene duplication and dimerization and each monomer has 12 helices. Yeast CM is allosterically activated by Trp and inhibited by Tyr [].
Chorismate mutase (CM) is a regulatory enzyme () required for biosynthesis of the aromatic amino acids phenylalanine and tyrosine. CM catalyzes the Claisen rearrangement of chorismate to prephenate, which can subsequently be converted to precursors of either L-Phe or L-Tyr. In bifunctional enzymes the CM domain can be fused to a prephenate dehydratase (P-protein for Phe biosynthesis), to a prephenate dehydrogenase (T-protein, for Tyr biosynthesis), or to 3-deoxy-D-arabino-heptulosonate 7-phosphate (DAHP) synthase (). Besides these prokaryotic bifunctional enzymes, monofunctional CMs occur in prokaryotes as well as in fungi, plants and nematode worms [].The type I or AroH class of CM is represented by Bacillus subtilis aroH, a monofunctional, nonallosteric, homotrimeric enzyme characterized by its pseudo-alpha/β-barrel 3D structure. Each monomer folds into a 5-stranded mixed β-sheet packed against an α-helix and a 3-10 helix. The core is formed by a closed barrel of mixed β-sheets surrounded by helices. The interfaces between adjacent subunits form three equivalent clefts that harbor the active sites [].The type II or AroQ class of CM has a completely different all-helical 3D structure, represented by the CM domain of the bifunctional Escherichia coli P-protein. This type is named after the Enterobacter agglomerans monofunctional CM encoded by the aroQ gene []. All CM domains from bifunctional enzymes as well as most monofunctional CMs belong to this class, including archaeal CM.Eukaryotic CM from plants and fungi form a separate subclass of AroQ, represented by the Baker's yeastallosteric CM []. These enzymes show only partial sequence similarity to the prokaryotic CMs due to insertions of regulatory domains, but the helix-bundle topology and catalytic residues are conserved and the 3D structure of the E. coli CM dimer resembles a yeast CM monomer [, , ]. The E. coli P-protein CM domain consists of 3 helices and lacks allosteric regulation. The yeast CM has evolved by gene duplication and dimerization and each monomer has 12 helices. Yeast CM is allosterically activated by Trp and inhibited by Tyr [].This entry represents chorismate mutase from eukaryotes.
This domain includes the C-terminal domain from the fungal alpha aminoadipate reductase enzyme (also known as aminoadipate semialdehyde dehydrogenase) which is involved in the biosynthesis of lysine [], as well as the reductase-containing component of the myxochelin biosynthetic gene cluster, MxcG []. The mechanism of reduction involves activation of the substrate by adenylation and transfer to a covalently-linked pantetheine cofactor as a thioester. This thioester is then reduced to give an aldehyde (thus releasing the product) and a regenerated pantetheine thiol []; in myxochelin biosynthesis this aldehyde is further reduced to an alcohol or converted to an amine by an aminotransferase. This is a fundamentally different reaction than beta-ketoreductase domains of polyketide synthases which act at a carbonyl two carbons removed from the thioester and forms an alcohol as a product. The majority of bacterial sequences containing this domain are non-ribosomal peptide synthetases in which this domain is similarly located proximal to a thiolation domain. In some cases this domain is found at the end of a polyketide synthetase enzyme, but is unlike ketoreductase domains which are found before the thiolase domains. Exceptions to this observed relationship with the thiolase domain include three proteins which consist of stand-alone reductase domains (from Mycobacterium leprae, Anabaena and from Streptomyces coelicolor) and one protein (from Nostoc) which contains N-terminal homology with a small group of hypothetical proteins but no evidence of a thiolation domain next to the putative reductase domain.This family consists of a short-chain dehydrogenase/reductase (SDR) module of multidomain proteins identified as putative polyketide sythases fatty acid synthases (FAS), and nonribosomal peptide synthases, among others. However, unlike the usual ketoreductase modules of FAS and polyketide synthase, these domains are related to the extended SDRs, and have canonical NAD(P)-binding motifs and an active site tetrad. Extended short-chain dehydrogenases/reductases (SDRs) are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central β-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG].XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif [, , , , , , , ].
Lipopolysaccharides (LPS) are glycolipids that consitutes the outer monolayer of the outer membranes of most Gram-negative bacteria []. They consist of lipid A (endotoxin) which anchors LPS to the outer membrane, a non-repeating core oligosachharide, and an immunogenic O-antigen repeat polymer, which is an oligosaccharide of 1-40 units that variesbetween different strains of bacteria. Although the O-antigen and most of the core domain are not necessary for growth in the lab, they appear to help bacteria resist environmental stresses including the complement system and antibiotics.This family consists of examples of ADP-L-glycero-D-mannoheptose-6-epimerase, an enzyme involved in biosynthesis of the inner core of LPS in Gram-negative bacteria []. This enzyme is homologous to UDP-glucose 4-epimerase () and belongs to the NAD dependent epimerase/dehydratase family. It participates in the biosynthetic pathway leading to incorporation of heptose, a conserved sugar, into the core region of LPS, performing the NAD-dependent reaction shown below:ADP-D-glycero-D-manno-heptose = ADP-L-glycero-D-manno-heptoseIt is a homopentameric enzyme with each monomer composed of two domains: an N-terminal modified Rossman fold domain for NADP binding, and a C-terminal substrate binding domain. This subgroup has the canonical active site tetrad and NAD(P)-binding motif [].Extended short-chain dehydrogenases/reductases (SDRs) are distinct from classical SDRs. In addition to the Rossmann fold (alpha/beta folding pattern with a central β-sheet) core region typical of all SDRs, extended SDRs have a less conserved C-terminal extension of approximately 100 amino acids. Extended SDRs are a diverse collection of proteins, and include isomerases, epimerases, oxidoreductases, and lyases; they typically have a TGXXGXXG cofactor binding motif. SDRs are a functionally diverse family of oxidoreductases that have a single domain with a structurally conserved Rossmann fold, an NAD(P)(H)-binding region, and a structurally diverse C-terminal region. Sequence identity between different SDR enzymes is typically in the 15-30% range; they catalyze a wide range of activities including the metabolism of steroids, cofactors, carbohydrates, lipids, aromatic compounds, and amino acids, and act in redox sensing. Classical SDRs have an TGXXX[AG].XG cofactor binding motif and a YXXXK active site motif, with the Tyr residue of the active site motif serving as a critical catalytic residue (Tyr-151, human 15-hydroxyprostaglandin dehydrogenase numbering). In addition to the Tyr and Lys, there is often an upstream Ser and/or an Asn, contributing to the active site; while substrate binding is in the C-terminal region, which determines specificity. The standard reaction mechanism is a 4-pro-S hydride transfer and proton relay involving the conserved Tyr and Lys, a water molecule stabilized by Asn, and nicotinamide. Atypical SDRs generally lack the catalytic residues characteristic of the SDRs, and their glycine-rich NAD(P)-binding motif is often different from the forms normally seen in classical or extended SDRs. Complex (multidomain) SDRs such as ketoreductase domains of fatty acid synthase have a GGXGXXG NAD(P)-binding motif and an altered active site motif (YXXXN). Fungal type ketoacyl reductases have a TGXXXGX(1-2)G NAD(P)-binding motif [, , , , , , , ].
The short peptides that forms cross-links between glycan chains in the peptidoglycan polymer in bacterial cell walls require d-amino acids (DAA), being d-Alanine and d-Glutamate the most predominant ones. DAA are generated from the l-enantiomers by specific alanine and glutamate racemases. However, diverse bacteria can produce non-canonical DAA (NCDAA) components of the cell wall, that relies on periplasmic broad-spectrum racemases (Bsr) activity. Lysine racemase is another enzyme present in some organisms and catalyses the conversion of l-Lys to d-Lys but it also can use l-Arg as substrate. Together with Bsr they are classified as Group III racemases []. These NCDAA are involved in different cellular processes including biofilm stability, sporulation and cell communication and allow pathogenic bacteria to adapt in adverse environments []. Sequence studies revealed that Bsr and Lyr contained catalytic Lys and Tyr residues at equivalent positions to that in alanine racemases [, ]. Structural analyses between Bsr from Vibrio cholerae (BsrV) and more restricted enzymes revealed that it exhibits a wider entry site and channel which may facilitate interaction with amino-acid substrates larger than alanine. The catalytic site of BsrV-like racemases is more relaxed that those of related alanine racemases, which is probably due to differences on chamber components and to different interactions of the enzymatic domains to form them [, ]. Crystal structure of Lyr revealed a similar fold of alanine racemases containing an N-terminal α-β barrel and a C-terminal β-stranded domain [].
In eukaryotes, glutathione S-transferases (GSTs) participate in the detoxification of reactive electrophilic compounds by catalysing theirconjugation to glutathione. The GST domain is also found in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli. The major lens polypeptide of Cephalopoda is also a GST [, , , ].Bacterial GSTs of known function often have a specific, growth-supporting role in biodegradative metabolism: epoxide ring opening and tetrachlorohydroquinone reductive dehalogenation are two examples of the reactions catalysed by these bacterial GSTs. Some regulatory proteins, like the stringent starvation proteins, also belong to the GST family [, ]. GST seems to be absent from Archaea in which gamma-glutamylcysteine substitute to glutathione as major thiol.Soluble GSTs activate glutathione (GSH) to GS-. In many GSTs, this is accomplished by a Tyr at H-bonding distance from the sulphur of GSH. These enzymes catalyse nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic carbon, nitrogen, or sulphur atom [].Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The homodimeric enzymes display a conserved structural fold, with each monomer composed of two distinct domains []. The N-terminal domain forms a thioredoxin-like fold that binds the glutathione moiety, while the C-terminal domain contains several hydrophobic α-helices that specifically bind hydrophobic substrates.This entry represents the N-terminal domain of GST.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This represents serine/threonine-protein kinases (), such as Ulk1 and Ulk2 (Unc-51-Like Kinase). Ulk1 and Ulk2 regulate filopodia extension and branching of sensory axons. They are important for axon growth, playing an essential role in neurite extension of cerebellar granule cells [, ].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents serine/threonine-protein kinases (), such as Sbk1. Sbk1 may be involved in signal-transduction pathways related to the control of brain development, such as the control of neuronal proliferation or migration in the brain of embryos.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents predicted serine/threonine-protein kinases () such as PknK.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents proteins predicted to be serine/threonine-protein kinases (), such as YKL116C from Saccharomyces cerevisiae (Baker's yeast).
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents serine/threonine-protein kinases () with pentapeptide domains, such as SpkB from Synechocystis sp. (strain PCC 6803). SpkB is required for cell motility [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a numberof diseases [].This enry represents a serine/threonine-protein kinase () found in Asfivirus such as African swine fever virus (ASFV). These enzymes are essential for viral replication and may mediate the virus' progression through DNA replication [].
In eukaryotes, glutathione S-transferases (GSTs) participate in the detoxification of reactive electrophilic compounds by catalysing theirconjugation to glutathione. The GST domain is also found in S-crystallins from squid, and proteins with no known GST activity, such as eukaryotic elongation factors 1-gamma and the HSP26 family of stress-related proteins, which include auxin-regulated proteins in plants and stringent starvation proteins in Escherichia coli. The major lens polypeptide of Cephalopoda is also a GST [, , , ].Bacterial GSTs of known function often have a specific, growth-supporting role in biodegradative metabolism: epoxide ring opening and tetrachlorohydroquinone reductive dehalogenation are two examples of the reactions catalysed by these bacterial GSTs. Some regulatory proteins, like the stringent starvation proteins, also belong to the GST family [, ]. GST seems to be absent from Archaea in which gamma-glutamylcysteine substitute to glutathione as major thiol.Soluble GSTs activate glutathione (GSH) to GS-. In many GSTs, this is accomplished by a Tyr at H-bonding distance from the sulphur of GSH. These enzymes catalyse nucleophilic attack by reduced glutathione (GSH) on nonpolar compounds that contain an electrophilic carbon, nitrogen, or sulphur atom [].Glutathione S-transferases form homodimers, but in eukaryotes can also form heterodimers of the A1 and A2 or YC1 and YC2 subunits. The homodimeric enzymes display a conserved structural fold, with each monomer composed of two distinct domains []. The N-terminal domain forms a thioredoxin-like fold that binds the glutathione moiety, while the C-terminal domain contains several hydrophobic α-helices that specifically bind hydrophobic substrates.
A carbohydrate-binding module (CBM) is defined as a contiguous amino acid sequence within a carbohydrate-active enzyme with a discreet fold having carbohydrate-binding activity. A few exceptions are CBMs in cellulosomal scaffolding proteins and rare instances of independent putative CBMs. The requirement of CBMs existing as modules within larger enzymes sets this class of carbohydrate-binding protein apart from other non-catalytic sugar binding proteins such as lectins and sugar transport proteins.CBMs were previously classified as cellulose-binding domains (CBDs) based on the initial discovery of several modules that bound cellulose [, ]. However, additional modules in carbohydrate-active enzymes are continually being found that bind carbohydrates other than cellulose yet otherwise meet the CBM criteria, hence the need to reclassify these polypeptides using more inclusive terminology.Previous classification of cellulose-binding domains were based on amino acid similarity. Groupings of CBDs were called "Types"and numbered with roman numerals (e.g. Type I or Type II CBDs). In keeping with the glycoside hydrolase classification, these groupings are now called families and numbered with Arabic numerals. Families 1 to 13 are the same as Types I to XIII. For a detailed review on the structure and binding modes of CBMs see [].This entry represents , which binds starch. The crystal structure of CBM20 has been solved []. It consists of seven β-strands forming an open-sided distorted β-barrel. Several aromatic residues, especially the well-conserved Trp and Tyr residues, participate in granular starch binding.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This group represents a protein kinase C, alpha/beta/gamma types.
The alternative oxidase (AOX) is an enzyme that forms part of the electron transport chain in mitochondria of different organisms [, ]. Proteins homologous to the mitochondrial oxidase have also been identified in bacterial genomes [, ]. The oxidase provides an alternative route for electrons passing through the electron transport chain to reduce oxygen. However, as several proton-pumping steps are bypassed in this alternative pathway, activation of the oxidase reduces ATP generation. This enzyme was first identified as a distinct oxidase pathway from cytochrome c oxidase as the alternative oxidase is resistant to inhibition by the poison cyanide [].The alternative oxidase (also known as ubiquinol oxidase) is used as a second terminal oxidase in the mitochondria, electrons are transferred directly from reduced ubiquinol to oxygen forming water []. This is not coupled to ATP synthesis and is not inhibited by cyanide, this pathway is a single step process []. In Oryza sativa (rice) the transcript levels of the alternative oxidase are increased by low temperature []. It has been predicted to contain a coupled diiron centre on the basis of a conserved sequence motif consisting of the proposed iron ligands, four Glu and two His residues []. The EPR study of Arabidopsis thaliana (mouse-ear cress) alternative oxidase AOX1a shows that the enzyme contains a hydroxo-bridged mixed-valent Fe(II)/Fe(III) binuclear iron centre []. A catalytic cycle has been proposed that involves a di-iron centre and at least one transient protein-derived radical, most probably an invariant Tyr residue [].
The arginine dihydrolase (AD) pathway is found in many prokaryotes and some primitive eukaryotes, an example of the latter being Giardia lamblia (Giardia intestinalis) []. The three-enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon dioxide and ammonia. In simpler bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein [].Most prokaryotic arginine deiminase pathways are under the control of a repressor gene, termed ArgR []. This is a negative regulator, and will only release the arginine deiminase operon for expression in the presence of arginine []. The crystal structure of apo-ArgR from Bacillus stearothermophilus has been determined to 2.5A by means of X-ray crystallography []. The protein exists as a hexamer of identical subunits, and is shown to have six DNA-binding domains, clustered around a central oligomeric core when bound to arginine. It predominantly interacts with A.T residues in ARG boxes. This hexameric protein binds DNA at its N terminus to repress arginine biosyntheis or activate arginine catabolism. Some species have several ArgR paralogs. In a neighbour-joining tree, some of these paralogous sequences show long branches and differ significantly from the well-conserved C-terminal region. The C-terminal domain of the arginine repressor is responsible for arginine binding and multimerization [, ]. It can also bind ornithine, Pro and Tyr (Matilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the catalytic domain found in a number of serine/threonine- and tyrosine-protein kinases. It does not include catalytic domain of dual specificity kinases.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Diacylglycerol (DAG) is a second messenger that acts as a protein kinase C activator. The DAG kinase domain is assumed to be an accessory domain. Upon cell stimulation, DAG kinase converts DAG into phosphatidate, initiating the resynthesis of phosphatidylinositols and attenuating protein kinase C activity. It catalyses the reaction: ATP + 1,2-diacylglycerol = ADP +1,2-diacylglycerol 3-phosphate. The enzyme is stimulated by calcium and phosphatidylserine and phosphorylated by protein kinase C. This domain is always associated with .
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This domain is found in a large variety of protein kinases with different functions and dependencies. Protein kinase C, for example, is a calcium-activated, phospholipid-dependent serine- and threonine-specific enzyme. It is activated by diacylglycerol which, in turn, phosphorylates a range of cellular proteins. This domain is most often found associated with .
Human protein-tyrosine kinase-6 (PTK6, also known as breast tumor kinase (Brk)) is a member of the non-receptor protein-tyrosine kinase family and is expressed in two-thirds of all breast tumours []. PTK6 contains an SH3 domain, an SH2 domain, and catalytic domains. For the case of the non-receptor protein-tyrosine kinases, the SH2 domain is typically involved in negative regulation of kinase activity by binding to a phosphorylated tyrosine residue near to the C terminus. The C-terminal sequence of PTK6 (PTSpYENPT where pY is phosphotyrosine) is thought to be a self-ligand for the SH2 domain []. This entry represents the SH2 domain of PTK6. The structure of this domain resembles other SH2 domains except for a centrally located four-stranded antiparallel β-sheet (strands betaA, betaB, betaC, and betaD). There are also differences in the loop length which might be responsible for PTK6 ligand specificity []. There are two possible means of regulation of PTK6: autoinhibitory with the phosphorylation of Tyr playing a role in its negative regulation and autophosphorylation at this site, though it has been shown that PTK6 might phosphorylate signal transduction-associated proteins Sam68 and signal transducing adaptor family member 2 (STAP/BKS) in vivo [].
Pyruvate carboxylase () (PC), a member of the biotin-dependent enzyme family, is involved in gluconeogenesis by mediating thecarboxylation of pyruvate to oxaloacetate. Biotin-dependent carboxylase enzymes perform a two step reaction. Enzyme-bound biotin is first carboxylated by bicarbonate and ATP and the carboxyl group temporarily bound to biotin is subsequently transferred to an acceptor substrate such as pyruvate []. PC has three functional domains: a biotin carboxylase (BC) domain, a carboxyltransferase (CT) domain which perform the second part of the reaction and a biotinyl domain [, ]. The pyruvate binding to the CT active site induces a conformational change stabilised by the interaction of conserved Asp and Tyr residues in this domain which leads to the formation of the biotin binding pocket and ensures the efficient coupling of BC and CT domain reactions []. The mechanism by which the carboxyl group is transferred from the carboxybiotin to the pyruvate is not well understood.The pyruvate carboxyltransferase domain is also found in other pyruvate binding enzymes and acetyl-CoA dependent enzymes suggesting that this domain can be associated with different enzymatic activities.This domain is found towards the N-terminal region of various aldolase enzymes. This N-terminal TIM barrel domain []interacts with the C-terminal domain. The C-terminal DmpG_comm domain () is thought to promote heterodimerization with members of to form a bifunctional aldolase-dehydrogenase [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structureshave been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents 3-deoxy-D-manno-octulosonic acid kinase, which is responsible for the ATP-dependent phosphorylation of 3-deoxy-D-manno-octulosonic acid at the 4-OH position during lipopolysaccharide core biosynthesis.
Terminase large subunit (TerL) from bacteriophages and evolutionarily related viruses, is an important component of the DNA packing machinery and comprises an ATPase domain, which powers DNA translocation and a nuclease domain that cuts concatemeric DNA [, , ]. TerL forms pentamers in which the ATPase domains form a ring distal to the capsid. The ATPase domain contains a C-terminal subdomain that sits above the ATPase active site, called the "Lid subdomain"with reference to analogous lid subdomains found in other ATPases []. It contains a hydrophobic patch (Trp and Tyr residues) that mediates critical interactions in the interface between adjacent ATPase subunits and assists the positioning of the arginine finger residue that catalyses ATP hydrolysis []. The endonuclease cuts concatemeric DNA first in the initiation phase in a sequence specific site and later in the completion stage of the DNA packaging process when the capsid is full [, ]. Cryo-EM studies indicate that TerL forms a pentamer that binds to a dodecameric assembly called portal and attaches to the capsid. It has been proposed that nuclease domains form a radially arranged ring that is proximal to portal, playing a key role in pentamer assembly []. The nuclease domain has a RNAse H-like fold and it has been proposed to utilise a two-metal catalysis mechanism like in other RNAse H-like endonucleases such as RNase H, transposases, retroviral integrases and RuvC Holliday junction resolvases []. This entry also includes uncharacterised bacterial sequences.
PTKs catalyse the transfer of the gamma-phosphoryl group from ATP to tyrosine (tyr) residues in protein substrates. Itk, also known as Tsk or Emt, is a member of the Tec-like subfamily of proteins, which are cytoplasmic (or nonreceptor) PTKs with similarity to Src kinases in that they contain Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Unlike Src kinases, most Tec subfamily members except Rlk also contain an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation. In addition, Itk contains the Tec homology (TH) domain containing one proline-rich region and a zinc-binding region [, ].Itk is expressed in T-cells and mast cells, and is important in their development and differentiation []. Of the three Tec kinases expressed in T-cells, Itk plays the predominant role in T-cell receptor (TCR) signalling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signalling of the T-cell costimulatory receptor CD28, the T-cell surface receptor CD2, and the chemokine receptor CXCR4 [, ]. In addition, Itk is crucial for the development of T-helper(Th)2 effector responses [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the lipopolysaccharide core heptose(I) kinase RfaP, which is required for the addition of phosphate to O-4 of the first heptose residue of the lipopolysaccharide (LPS) inner core region. It has previously been shown that RfaP is necessary for resistance to hydrophobic and polycationic antimicrobials in Escherichia coli, and that it is required for virulence in invasive strains of S. enterica [].
The arginine dihydrolase (AD) pathway is found in many prokaryotes and some primitive eukaryotes, an example of the latter being Giardia lamblia (Giardia intestinalis) []. The three-enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon dioxide and ammonia. In simpler bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein [].Most prokaryotic arginine deiminase pathways are under the control of a repressor gene, termed ArgR []. This is a negative regulator, and will only release the arginine deiminase operon for expression in the presence of arginine []. The crystal structure of apo-ArgR from Bacillus stearothermophilus has been determined to 2.5A by means of X-ray crystallography []. The protein exists as a hexamer of identical subunits, and is shown to have six DNA-binding domains, clustered around a central oligomeric core when bound to arginine. It predominantly interacts with A.T residues in ARG boxes. This hexameric protein binds DNA at its N terminus to repress arginine biosyntheis or activate arginine catabolism. Some species have several ArgR paralogs. In a neighbour-joining tree, some of these paralogous sequences show long branches and differ significantly from the well-conserved C-terminal region. The C-terminal domain of the arginine repressor is responsible for arginine binding and multimerization [, ]. It can also bind ornithine, Pro and Tyr (Matilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
This entry represents death-associated protein kinases 1 (DAPK1). It act as a positive regulator of apoptosis [, , , , ]. Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].
Amino acid permeases are integral membrane proteins involved in the transportof amino acids into the cell. A number of such proteins have been found to beevolutionary related [, , ].Aromatic amino acids are concentrated in the cytoplasm of Escherichia coli by 4 distinct transport systems: a general aromatic amino acid permease, and aspecific permease for each of the 3 types (Phe, Tyr and Trp) []. It has been shown []that some permeases in E. coli and related bacteria are evolutionary related.These permeases are proteins of about 400 to 420 amino acids and are located in the cytoplasmic membrane and, like bacterial sugar/cation transporters, are thought to contain 12 transmembrane (TM)regions []- hydropathy analysis, however, is inconclusive, suggesting thepossibility of 10 to 12 membrane-spanning domains []. The best conserved domain is a stretch of 20 residues which seems to be located in a cytoplasmic loop between thefirst and second transmembrane region.This family is specific for aromatic amino acid transporters and includes the tyrosine permease, TyrP (), and the tryptophan transporters TnaB () and Mtr () of E. coli.
Aromatic ring hydroxylating dioxygenases are multicomponent 1,2-dioxygenase complexes that convert closed-ring structures to non-aromatic cis-diols []. The complex has both hydroxylase and electron transfer components. The hydroxylase component is itself composed of two subunits: an alpha-subunit of about 50kDa, and a beta-subunit of about 20kDa. The electron transfer component is either composed of two subunits: a ferredoxin and a ferredoxin reductase or by a single bifunctional ferredoxin/reductase subunit. Sequence analysis of hydroxylase subunits of ring hydroxylating systems (including toluene, benzene and napthalene 1,2-dioxygenases) suggests they are derived from a common ancestor []. The alpha-subunit binds both a Rieske-like 2Fe-2S cluster and an iron atom: conserved Cys and His residues in the N-terminal region may provide 2Fe-2S ligands, while conserved His and Tyr residues may coordinate the iron. The beta subunit may be responsible for the substrate specificity of the dioxygenase system [].This entry represents the conserved C-terminal domain found in the alpha subunit of aromatic-ring-hydroxylating dioxygenases. It is the catalytic domain of aromatic-ring- hydroxylating dioxygenase systems. The active site contains a non-heme ferrous ion coordinated by three ligands.
Aromatic ring hydroxylating dioxygenases are multicomponent 1,2-dioxygenase complexes that convert closed-ring structures to non-aromatic cis-diols []. The complex has both hydroxylase and electron transfer components. The hydroxylase component is itself composed of two subunits: an alpha-subunit of about 50kDa, and a beta-subunit of about 20kDa. The electron transfer component is either composed of two subunits: a ferredoxin and a ferredoxin reductase or by a single bifunctional ferredoxin/reductase subunit. Sequence analysis of hydroxylase subunits of ring hydroxylating systems (including toluene, benzene and napthalene 1,2-dioxygenases) suggests they are derived from a common ancestor []. The alpha-subunit binds both a Rieske-like 2Fe-2S cluster and an iron atom: conserved Cys and His residues in the N-terminal region may provide 2Fe-2S ligands, while conserved His and Tyr residues may coordinate the iron. The beta subunit may be responsible for the substrate specificity of the dioxygenase system [].The alpha-subunit of the hydroxylase components bind both a 2Fe-2S type iron-sulphur centre and an iron atom. There is, in the N-terminal section of these proteins, a conserved region of 24 residues which contains two cysteines and two histidines which have been shown to be involved in the binding of the iron-sulphur centre [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].The protein kinase D family of enzymes consists of three isoforms: PKD1 (PKCmu), PKD2, and PKD3 (PKCnu). They all share a similar architecture with regulatory sub-domains that play specific roles in the activation, translocation and function of the enzymes. The PKD enzymes have recently been implicated in very diverse cellular functions, including Golgi organisation and plasma membrane directed transport, metastasis, immune responses, apoptosis and cell proliferation []. Each isoform is differentially regulated through phosphorylation [].
Btk (Bruton tyrosine kinase) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. Btk also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation, and the Tec homology (TH) domain with proline-rich and zinc-binding regions [].Btk is expressed in B-cells, and a variety of myeloid cells including mast cells, platelets, neutrophils, and dendrictic cells [, ]. It interacts with a variety of partners, from cytosolic proteins to nuclear transcription factors, suggesting a diversity of functions. Stimulation of a diverse array of cell surface receptors, including antigen engagement of the B-cell receptor (BCR), leads to PH-mediated membrane translocation of Btk and subsequent phosphorylation by Src kinase and activation []. Btk plays an important role in the life cycle of B-cells including their development, differentiation, proliferation, survival, and apoptosis []. Mutations in Btk cause the primary immunodeficiency disease, X-linked agammaglobulinaemia (XLA) in humans [, ]. This entry represents the SH3 domain of Btk.
ITK (also known as Tsk or Emt) is a member of the Tec family, which is a group of nonreceptor tyrosine kinases containing Src homology protein interaction domains (SH3, SH2) N-terminal to the catalytic tyr kinase domain. It also contains an N-terminal pleckstrin homology (PH) domain, which binds the products of PI3K and allows membrane recruitment and activation [], and the Tec homology (TH) domain, which contains proline-rich and zinc-binding regions. ITK is expressed in T-cells and mast cells, and is important in their development and differentiation [, ]. Of the three Tec kinases expressed in T-cells, ITK plays the predominant role in T-cell receptor (TCR) signaling. It is activated by phosphorylation upon TCR crosslinking and is involved in the pathway resulting in phospholipase C-gamma1 activation and actin polymerization []. It also plays a role in the downstream signaling of the T-cell costimulatory receptor CD28 [], the T-cell surface receptor CD2 [], and the chemokine receptor CXCR4 []. In addition, ITK is crucial for the development of T-helper(Th)2 effector responses []. This entry represents the SH3 domain of ITK.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This domain is found at the C terminus of the Calcium/calmodulin dependent protein kinases II (CaMKII). These proteins also have a Ser/Thr protein kinase domain () at their N terminus []. The function of the CaMKII association domain is the assembly of the single proteins into large (8 to 14 subunits) multimers []and is a prominent kinase in the central nervous system that may function in long-term potentiation and neurotransmitter release.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry contains the PknD family of serine/threonine protein kinases which are found in (for example) C. trachomatis. In conjunction with Pkn1 they may play a role in specific interactions with host proteins during intracellular growth [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents RIO kinase, they exhibit little sequence similarity with eukaryotic protein kinases, and are classified as atypical protein kinases []. The conformation of ATP when bound to the RIO kinases is unique when compared with ePKs, such as serine/threonine kinases or the insulin receptor tyrosine kinase, suggesting that the detailed mechanism by which the catalytic aspartate of RIO kinases participates in phosphoryl transfer may not be identical to that employed in known serine/threonine ePKs. Representatives of the RIO family are present in organisms varying from Archaea to humans, although the RIO3 proteins have only been identified in multicellular eukaryotes, to date. Yeast Rio1 and Rio2 proteins are required for proper cell cycle progression and chromosome maintenance, and are necessary for survival of the cells. These proteins are involved in the processing of 20 S pre-rRNA via late 18 S rRNA processing.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This group represents a membrane-associated tyrosine- and threonine-specific Cdc2-inhibitory kinase.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This group represents a tyrosine-protein kinase, Ret receptor type.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This group represents a group of known and predicted receptor-type tyrosine-protein kinases, including the EGF and ERB receptors, and the melanoma-inducing oncogene product XmrK.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents the receptor tyrosine kinases for HGF (hepatocyte growth factor) and MSP (macrophage-stimulating protein) []. The HGF receptor functions in cell proliferation, scattering, morphogenesis and survival [, ].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].This entry represents Fes/Fps family of non-receptor tyrosine kinases.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments ofa number of diseases [].Eukaryotic protein kinases [, , , , ]are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is a glycine-rich stretch of residues in the vicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue which is important for the catalytic activity of the enzyme [].This entry represents the protein kinase domain containing the catalytic function of protein kinases []. This domain is found in serine/threonine-protein kinases, tyrosine-protein kinases and dual specificity protein kinases.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents a protein encoded by the bacteriophage T7 early gene 0.7. This gene is dispensible in a fast-growing host, but is essential when the host is growing suboptimally. The protein is bifunctional, with the C-terminal third involved in host transcription shut-off, while the N-terminal two-thirds has protein kinase activity and is capable of phosphorylating a number of host cell proteins and itself []. Expression of the protein kinase in the host leads to the phosphorylation of host RNAse E and the stabilisation of phage mRNA.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Phosphorylase B kinase () belongs to a family of proteins involved in glycogen biosynthesis []. The protein has a subunit compositionof (alpha, beta, gamma, delta)4, where the alpha and beta subunits are regulatory, delta is calmodulin, and the gamma subunit is catalytic. The enzyme is believed to have a dual role, the first is connected with glycogendegradation via phosphorylation of glycogen phosphorylase; the second controls glycogen biosynthesis on the sarcoplasmic reticular membrane moredirectly by phosphorylation, and thus inhibition, of glycogen synthase [].The gamma catalytic chain contains three domains; one protein kinase and twocalmodulin-binding domains. Calcium and magnesium ions, together with cyclicAMP, positively affect the efficiency of the enzyme, which is believed to be associated with its auto-kinase activity [, ].The full extent of the effects of deficiencies in this enzyme in humans is unknown; but case studies have been documented [, , ]that detail symptoms asmild as 'exercise intolerance' [], to infant mortality arising from floppyinfant syndrome [].
Angiotensin II is a blood-borne hormone produced in the circulation, it is also formed in many tissues such as the brain, kidney, heart, and blood vessels, where angiotensin II functions as a paracrine and autocrine hormone. The known actions of angiotensin II are mediated through two angiotensin receptor subtypes, Angiotensin II receptor 1 and angiotensin II receptor 2, which are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family. These subtypes are important in the renin-angiotensin system, as they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II []. They also stimulate increased fluid intake and regulate the neuroendocrine system [].This entry represents angiotensin II receptor type 2 (AT2), which plays an important role in the CNS and cardiovascular functions mediated by the renin-angiotensin system. The AT2 receptor is highly expressed in various foetal tissues, with lower levels in the brain and reproductive tissues []. It appears to be up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing [, , , ]. Depending on the tissue type, activation of the AT2 receptor also appears to stimulate intracellular mechanisms involving Tyr and Ser/Thr phosphatases, which leads to the inactivation of the AT1 and growth factor activated kinases [, , , , , , ]. However, when inducing cell differentiation, the AT2 receptor can also stimulate MAP kinases Erk1/Erk2 []. As a consequence, there is an inactivation of MAP kinase, promotion of apoptosis, repolarization trough opening of delayed-rectifier K+ channels and calcium and voltage activated potassium channel, closing of T -type Ca2+ channels and vasodilation [, , , ]. Through its phosphatase activity, the AT2 receptor regulates the NF-kappaB pathway [, ]and interferes with the inflammatory process [, ]. The AT2 receptor does not require receptor phosphorylation or heterotrimeric G alpha/beta/gamma protein to be active [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].MAP (Mitogen Activated Protein) kinases participate in kinase cascades,whereby at least 3 protein kinases act in series, culminatingin activationof MAP kinase []. MAP kinases are activated by dual phosphorylationon both tyrosine and threonine residues of a conserved TXY motif.p38 proteins belong to the MAP kinase family and were discovered in 3different contexts independently: first, as tyrosine phosphoproteins foundin extracts of cells treated with inflammatory cytokines; second, astargets of a pyrinidyl imidazole drug that blocks production of TNFalpha; and third, as reactivating kinases for MAP kinase-activated protein(MAPKAP) []. The proteins are activated by cytokines, hormones, GPCRs,osmotic shock, heat shock and other stresses [].
The alternative oxidase (AOX) is an enzyme that forms part of the electron transport chain in mitochondria of different organisms [, ]. Proteins homologous to the mitochondrial oxidase have also been identified in bacterial genomes [, ]. The oxidase provides an alternative route for electrons passing through the electron transport chain to reduce oxygen. However, as several proton-pumping steps are bypassed in this alternative pathway, activation of the oxidase reduces ATP generation. This enzyme was first identified as a distinct oxidase pathway from cytochrome c oxidase as the alternative oxidase is resistant to inhibition by the poison cyanide [].The alternative oxidase (also known as ubiquinol oxidase) is used as a second terminal oxidase in the mitochondria, electrons are transferred directly from reduced ubiquinol to oxygen forming water []. This is not coupled to ATP synthesis and is not inhibited by cyanide, this pathway is a single step process []. In Oryza sativa (rice) the transcript levels of the alternative oxidase are increased by low temperature []. It has been predicted to contain a coupled diiron centre on the basis of aconserved sequence motif consisting of the proposed iron ligands, four Glu and two His residues []. The EPR study of Arabidopsis thaliana (mouse-ear cress) alternative oxidase AOX1a shows that the enzyme contains a hydroxo-bridged mixed-valent Fe(II)/Fe(III) binuclear iron centre []. A catalytic cycle has been proposed that involves a di-iron centre and at least one transient protein-derived radical, most probably an invariant Tyr residue [].The structure of alternative oxidase from Trypanosoma brucei has been solved. The enzyme is a homodimer with the nonhaem di-iron carboxylate active site buried within a four-helix bundle. In the inhibitor-free state, the di-iron carboxylate is ligated by four glutamate residues, but on binding of an inhibitor, a histidine is also induced to act as a ligand. A highly conserved tyrosine is close to the active site and required for activity []. This entry represents proteins with a structure similar to that of alternative oxidase.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Bone morphogenetic proteins (BMPs) regulate a wide range of cellular functions that contribute to embryonic development from mesoderm formation to organogenesis []. BMP type II receptor (BMPR2) transduces BMP signals from all BMPs by forming heteromeric complexes with and phosphorylating BMP type I receptors. Heterozygous germline mutations of BMPR-II gene in mice []complement the finding of BMPR-II mutations in patients with familial and sporadic primary pulmonary hypertension, indicating that BMPR-II may contribute to the maintenance of normal pulmonary vascular structure and function [, ].Mice with a smooth muscle-specific transgenic mouse expressing a dominant-negative BMPR-II under control of the tetracycline develop pulmonary hypertension []. Knockout studies have demonstrated that BMPR-II is essential for epiblast differentiation and mesoderm induction during early mouse development []. In contrast, knockout mice that express a BMPR-II lacking half of the ligand-binding domain die at midgestation with cardiovascular and skeletal defects [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents RIO kinase, they exhibit little sequence similarity with eukaryotic protein kinases, and are classified as atypical protein kinases []. The conformation of ATP when bound to the RIO kinases is unique when compared with ePKs, such as serine/threonine kinases or the insulin receptor tyrosine kinase, suggesting that the detailed mechanism by which the catalytic aspartate of RIO kinases participates in phosphoryl transfer may not be identical to that employed in known serine/threonine ePKs. Representatives of the RIO family are present in organisms varying from Archaea to humans, although the RIO3 proteins have only been identified in multicellular eukaryotes, to date. Yeast Rio1 and Rio2 proteins are required for proper cell cycle progression and chromosome maintenance, and are necessary for survival of the cells. These proteins are involved in the processing of 20 S pre-rRNA via late 18 S rRNA processing.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].This entry represents the salt-inducible protein kinases, SIK1 and SIK2, which are serine/threonine-protein kinases primarily activated by the master kinase LKB1 (STK11). SIK1 is involved in a variety of processes, such as cell cycle regulation, gluconeogenesis and lipogenesis regulation and muscle growth [, , , ]. SIK2 phosphorylates insulin receptor substrate-1 (IRS1) in insulin-stimulated adipocytes, potentially modulating the efficiency of insulin signal transduction, and may have a role in the development of insulin resistance in diabetes [. SIK1/2 inhibit CREB activity by phosphorylating and inhibiting activity of TORCs, the CREB-specific coactivators, like CRTC2/TORC2 and CRTC3/TORC3 in response to cAMP signalling [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic protein kinases [, , , , ]are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases.This entry represents a conserved site, which is located in the N-terminal extremity of the catalytic domain, where there is a glycine-rich stretch of residues in the vicinity of a lysine residue. It is this lysine residue that has been shown to be involved in ATP binding.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic protein kinases [, , , ]are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases.This group of genes codes for 9-kb striated preferentially expressed gene (SPEG)alpha and the 11-kb SPEGbeta found in skeletal muscle and heart. SPEGbeta encodes a 355kDa protein that contains two serine/threonine kinase domains and is homologous to proteins of the myosin light chain kinase family. At least one kinase domain is active and capable of autophosphorylation [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].TESK1 (testis-specific protein kinase 1) is a protein kinase with a structure composed of an N-terminal protein kinase domain and a C-terminal proline-rich domain and is most closely related to the LIM motif-containing protein kinase (LIMK) subfamily []. TESK1 has kinase activity with dual specificity on both serine/threonine and tyrosine residues []. When expressed in HeLa cells, TESK1 stimulates the formation of actin stress fibres and focal adhesions and functions downstream of integrins through phosphorylation and inactivation of cofilin []. In a yeast two-hybrid screen, Sprouty4 was identified as a binding partner of TESK1 [], and was subsequently found to negatively regulate cell spreading by inhibiting the kinase activity of TESK1 [].
This entry represents a domain found in various ephrin type A and B receptors, which have tyrosine kinase activity.Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specificinhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse thetransfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Eukaryotic protein kinases [, , , ]are enzymesthat belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. There are a number of conserved regions in the catalytic domain of protein kinases. In the N-terminal extremity of the catalytic domain there is aglycine-rich stretch of residues in thevicinity of a lysine residue, which has been shown to be involved in ATP binding. In the central part of the catalytic domain there is a conserved aspartic acid residue, which is important for the catalytic activity of the enzyme []. This signature contains the active site aspartate residue.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Tyrosine-protein kinases can transfer a phosphate group from ATP to a tyrosine residue in a protein. These enzymes can be divided into two main groups []:Receptor tyrosine kinases (RTK), which are transmembrane proteins involved in signal transduction; they play key roles in growth, differentiation, metabolism, adhesion, motility, death and oncogenesis []. RTKs are composed of 3 domains: an extracellular domain (binds ligand), a transmembrane (TM) domain, and an intracellular catalytic domain (phosphorylates substrate). The TM domain plays an important role in the dimerisation process necessary for signal transduction []. Cytoplasmic / non-receptor tyrosine kinases, which act as regulatory proteins, playing key roles in cell differentiation, motility, proliferation, and survival. For example, the Src-family of protein-tyrosine kinases [].TYK2 was first identified by low-stringency hybridisation screening of ahuman lymphoid cDNA library with the catalytic domain of proto-oncogene c-fms []. Mouse and puffer fish orthlogues have also been identified. In common with JAK1 and JAK2, and by contrast with JAK3, TYK2 appears to be ubiquitously expressed. This entry represents the N-terminal region of TYK2.
Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process. Protein kinases fall into three broad classes, characterised with respect to substrate specificity []:Serine/threonine-protein kinasesTyrosine-protein kinasesDual specificity protein kinases (e.g. MEK - phosphorylates both Thr and Tyr on target proteins)Protein kinase function is evolutionarily conserved from Escherichia coli to human []. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation []. Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved [], leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases [].Casein kinase, a ubiquitous, well-conserved protein kinase involved in cell metabolism and differentiation, is characterised by its preference for Ser or Thr in acidic stretches of amino acids. The enzyme is a tetramer of 2 alpha- and 2 beta-subunits [, ]. However, some species (e.g., mammals) possess 2 related forms of the alpha-subunit (alpha and alpha'), while others (e.g., fungi) possess 2 related beta-subunits (beta and beta') []. The alpha-subunit is the catalytic unit and contains regions characteristic of serine/threonine protein kinases. The beta-subunit is believed to be regulatory, possessing an N-terminal auto-phosphorylation site, an internal acidic domain, and a potential metal-binding motif []. The beta subunit is a highly conserved protein of about 25kDa that contains, in its central section, a cysteine-rich motif, CX(n)C, that could be involved in binding a metal such as zinc []. The mammalian beta-subunit gene promoter shares common features with those of other mammalian protein kinases and is closely related to the promoter of the regulatory subunit of cAMP-dependent protein kinase [].This superfamily represents the N-terminal α-helical domain, which has an orthogonal bundle topology.
