Nitronate monooxygenase (NMO), formerly referred to as 2-nitropropane dioxygenase (NPD) (), is an FMN-dependent enzyme that uses molecular oxygen to oxidise (anionic) alkyl nitronates and, in the case of the enzyme from Neurospora crassa, (neutral) nitroalkanes to the corresponding carbonyl compounds and nitrite. Previously classified as 2-nitropropane dioxygenase [, , ], but it is now recognised that this was the result of the slow ionisation of nitroalkanes to their nitronate (anionic) forms []. The enzymes from the fungus Neurospora crassa and the yeast Williopsis saturnus var. mrakii (formerly classified as Hansenula mrakii) contain non-covalently bound FMN as the cofactor. Active towards linear alkyl nitronates of lengths between 2 and 6 carbon atoms and, with lower activity, towards propyl-2-nitronate. The enzyme from N. crassa can also utilise neutral nitroalkanes, but with lower activity. One atom of oxygen is incorporated into the carbonyl group of the aldehyde product. The reaction appears to involve the formation of an enzyme-bound nitronate radical and an a-peroxynitroethane species, which then decomposes, either in the active site of the enzyme or after release, to acetaldehyde and nitrite.
Proteins in this entry are E3 ubiquitin-protein ligases that mediate ubiquitination and subsequent proteasomal degradation of target proteins. Proteins in this entry include Sina and Sinah (Sina homologue) from flies and SIAH1/2 from humans.The seven in absentia (sina) gene was first identified in Drosophila. The Drosophila Sina protein is essential for the determination of the R7 pathway in photoreceptor cell development: the loss of functional Sina results in the transformation of the R7 precursor cell to a non-neuronal cell type. The Sina protein contains an N-terminal RING finger domain C3HC4-type. Through this domain, Sina binds E2 ubiquitin-conjugating enzymes (UbcD1). Sina also interacts with Tramtrack (TTK88) via PHYL. Tramtrack is a transcriptional repressor that blocks photoreceptor determination, while PHYL down-regulates the activity of TTK88. In turn, the activity of PHYL requires the activation of the Sevenless receptor tyrosine kinase, a process essential for R7 determination. It is thought that Sina targets TTK88 for degradation, therefore promoting the R7 pathway. Murine and human homologues of Sina have also been identified. The human homologue SIAH1 []also binds E2 enzymes (UbcH5) and through a series of physical interactions, targets beta-catenin for ubiquitin degradation. Siah-1 expression is enhanced by p53, itself promoted by DNA damage.Thus this pathway links DNA damage to beta-catenin degradation [, ].
This domain is associated with the N terminus of members of the PHP superfamily, this includes: subunit of bacterial DNA polymerase III, eukaryotic DNA polymerase, X-family of DNA polymerases,histidinol phosphatases,and a number of uncharacterised protein families.In common for all PHP proteins is the presence of four conserved sequence motifs that contain invariant histidine and aspartate residues implicated in metal ion coordination. As part of DNA polymerases, the PHP domain was suggested to hydrolyse pyrophosphate and thereby shift the reaction equilibrium toward nucleotide polymerisation. However, it cannot be ruled out that the PHP domain possesses a nuclease activity, particularly in the repair polymerases of the X-family. No functional information is available for standalone proteins that belong to the PHP superfamily. The crystal structure of the YcdX protein from Escherichia coli has been determined to 1.6-A resolution. YcdX has an unusual topology of a α7-β7 barrel compared with the more common α8-β8 (TIM) barrel. The C-terminal helix caps the barrel on the N-terminal side. The deep cleft at the C-terminal side of the barrel contains the three zinc binding residues. These residues are invariant in the YcdX family confirming their functional importance. Only four proteins with known structures have a similar trinuclear zinc catalytic site. All four (nuclease P1, endonuclease IV, alkaline phosphatase, and phospholipase C) hydrolyse the phosphoester bond. This finding suggests a similar activity for YcdX. YcdX is among the genes significantly induced in response to the DNA damage, therefore indicating that members of the YcdX family may be involved in DNA repair [].
Kelch is a 50-residue motif, named after the Drosophila mutant in which it was first identified []. This sequence motif represents one β-sheet blade, and several of these repeats can associate to form a β-propeller. For instance, the motif appears 6 times in Drosophila egg-chamber regulatory protein (also known as ring canal kelch protein), creating a 6-bladed β-propeller. The motif is also found in mouse protein MIPP []and in a number of poxviruses. In addition, kelch repeats have been recognised in alpha- and beta-scruin [, ], and in galactose oxidase from the fungus Dactylium dendroides [, ]. The structure of galactose oxidase reveals that the repeated sequence corresponds to a 4-stranded antiparallel β-sheet motif that forms the repeat unit in a super-barrel structural fold [].The known functions of kelch-containing proteins are diverse: scruin is an actin cross-linking protein; galactose oxidase catalyses the oxidation of the hydroxyl group at the C6 position in D-galactose; and kelch may have a cytoskeletal function, as it is localised to the actin-rich ring canals that connect the 15 nurse cells to the developing oocyte in Drosophila []. Nevertheless, based on the location of the kelch pattern in the catalytic unit in galactose oxidase, functionally important residues have been predicted in glyoxal oxidase [].This entry represents a type of kelch sequence motif that comprises one β-sheet blade.
The hydroxycarboxylic acid receptors []are members of the rhodopsin-like G protein-coupled receptor (GPCR) family. There are three hydroxycarboxylic acid receptors, termed HCAR1-3. The family was formerly known as nicotinic acid receptor family, although nicotinic acid only shows submicromolar potency at HCAR2 [, ].The receptors respond to organic acids, including the endogenous short chain fatty acids, butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [, , ]. There is an increasing number of synthetic ligands mainly targeted at HCAR2 and HCAR3 receptors [, ]. All three receptors are expressed in adipocytes, and are coupled to Gi type G-proteins mediating antilipolytic effects in fat cells [, , , ]. HCAR2 and HCAR3 are also expressed in a variety of immune cells including monocytes, macrophages, neutrophils and Langerhans cells [, ]. HCAR1 and HCAR2 are found in most mammalian species, whereas HCAR3 is only present in higher primates []. There is evidence that these receptors can mediate anti-inflammatory effects. HCAR2 has been shown to be a receptor for the anti-dyslipidemic drug nicotinic acid (niacin) as well as for the anti-psoriatic drug monomethyl-fumarate [, ]. This entry represents hydroxycarboxylic acid receptor 1, also known as lactate receptor 1, G protein coupled receptor 104 and G-protein coupled receptor 81. The endogenous ligand for HCAR1 is L-lactic acid [].
The hydroxycarboxylic acid receptors []are members of the rhodopsin-like G protein-coupled receptor (GPCR) family. There are three hydroxycarboxylic acid receptors, termed HCAR1-3. The family was formerly known as nicotinic acid receptor family, although nicotinic acid only shows submicromolar potency at HCAR2 [, ].The receptors respond to organic acids, including the endogenous short chain fatty acids, butyric acid and L-lactic acid, as well as the lipid lowering agents nicotinic acid (niacin), acipimox and acifran [, , ]. There is an increasing number of synthetic ligands mainly targeted at HCAR2 and HCAR3 receptors [, ]. All three receptors are expressed in adipocytes, and are coupled to Gi type G-proteins mediating antilipolytic effects in fat cells [, , , ]. HCAR2 and HCAR3 are also expressed in a variety of immune cells including monocytes, macrophages, neutrophils and Langerhans cells [, ]. HCAR1 and HCAR2 are found in most mammalian species, whereas HCAR3 is only present in higher primates []. There is evidence that these receptors can mediate anti-inflammatory effects. HCAR2 has been shown to be a receptor for the anti-dyslipidemic drug nicotinic acid (niacin) as well as for the anti-psoriatic drug monomethyl-fumarate [, ]. This entry represents two members of hydroxycarboxylic acid receptor family, hydroxycarboxylic acid receptor 2 (also known as niacin receptor 1, G protein-coupled receptor 109A, nicotinic acid receptor, HM74A) and hydroxycarboxylic acid receptor 3 (also known as niacin receptor 2, G protein-coupled receptor 109B, low affinity nicotinic acid receptor). The endogenous ligands of HCAR2 and HCAR3 are beta-D-hydroxybutyric acid and 3-hydroxyoctanoic acid, respectively [].
This family was originally identified in Drosophila and called mago nashi, it is a strict maternal effect, grandchildless-like, gene []. The protein is an integral member of the exon junction complex (EJC). The EJC is a multiprotein complex that is deposited on spliced mRNAs after intron removal at a conserved position upstream of the exon-exon junction, and transported to the cytoplasm where it has been shown to influence translation, surveillance, and localization of the spliced mRNA. It consists of four core proteins (eIF4AIII, Barentsz [Btz], Mago, and Y14), mRNA, and ATP and is supposed to be a binding platform for more peripherally and transiently associated factors along mRNA travel. Mago and Y14 form a stable heterodimer that stabilizes the complex by inhibiting eIF4AIII's ATPase activity. Mago-Y14 heterodimer has been shown to interact with the cytoplasmic protein PYM, an EJC disassembly factor, and specifically binds to the karyopherin nuclear receptor importin 13 [, , , , , , , , , , , , , , , , ].The human homologue has been shown to interact with an RNA binding protein, ribonucleoprotein rbm8 () []. An RNAi knockout of the Caenorhabditis elegans homologue causes masculinization of the germ line (Mog phenotype) hermaphrodites, suggesting it is involved in hermaphrodite germ-line sex determination []but the protein is also found in hermaphrodites and other organisms without a sexual differentiation.
The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities []. Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini [].EMP-1, previously termed tumour-associated membrane protein (TMP), was originally isolated from a mouse brain tumour []. Human, rat and rabbit isoforms have also been identified. EMP-1 is expressed in a wide range of tissues, including heart, placenta, lung, skeletal muscle, kidney and small intestine []. A role for the protein in the control of cell growth has been suggested []. EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest []. In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest []. It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.
The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities []. Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini [].A role for the EMP family members in the control of cell growth has been suggested []. EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest []. In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest []. It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.EMP-2, previously termed XMP, was identified by expressed sequence tag (EST) database searching, pursuing sequences similar to EMP-1 []. Mus musculus (Mouse) and Homo sapiens (Human) isoforms have been cloned. EMP-2 is expressed in a range of tissues, including ovary, heart, lung and intestine. Although its function has not been elucidated, it has been postulated that EMP-2 may be involved in the regulation of cell proliferation on the basis of its sequence similarity to EMP-1 [].
The epithelial membrane proteins (EMP-1, -2 and -3), peripheral myelin protein 22 (PMP22), and lens fibre membrane intrinsic protein (LMIP) comprise a protein family on the basis of sequence and structural similarities []. Each family member is a small hydrophobic membrane glycoprotein, ~160-170 amino acids in length, and shares a common predicted transmembrane (TM) topology of 4 TM domains, with intracellular N- and C-termini [].A role for the EMP family members in the control of cell growth has been suggested []. EMP-1 is expressed at high levels in proliferating cells, and at reduced levels in cells undergoing growth arrest []. In contrast, PMP22, which is co-expressed with EMP-1 in a range of tissues, displays an inverse pattern of regulation, with high levels of expression in cultured cells undergoing growth arrest []. It has therefore been proposed that these proteins may have reciprocal functions in the control of cell quiescence and proliferation.EMP-3, previously termed YMP, was identified by expressed sequence tag (EST) database searching, pursuing sequences similar to EMP-1 []. Mouse, human and rat isoforms have been cloned. EMP-3 is expressed in a range of tissues, including peripheral blood leukocytes, ovary and intestine. Although its function has not been elucidated, it has been postulated that EMP-3 may be involved in the regulation of cell proliferation on the basis of its sequence similarity to EMP-1 [].
This entry represents the non-structural protein 6 (NSP6) from betacoronavirus. Recently, it was reported that SARS-CoV-2 NSP6 binds TANK binding kinase 1 (TBK1) to suppress interferon regulatory factor 3 (IRF3) phosphorylation which suppresses IFN-I signalling and production more efficiently than SARS-CoV and MERS-CoV [].Coronaviruses (CoV) redirect and rearrange host cell membranes as part of the viral genome replication and transcription machinery; they induce the formation of double-membrane vesicles in infected cells. CoV non-structural protein 6 (NSP6), a transmembrane-containing protein, together with NSP3 and NSP4, have the ability to induce double-membrane vesicles that are similar to those observed in severe acute respiratory syndrome (SARS) coronavirus-infected cells []. By itself, NSP6 can generate autophagosomes from the endoplasmic reticulum. Autophagosomes are normally generated as a cellular response to starvation to carry cellular organelles and long-lived proteins to lysosomes for degradation. Degradation through autophagy may provide an innate defense against virus infection, or conversely, autophagosomes can promote infection by facilitating the assembly of replicase proteins []. In additionto initiating autophagosome formation, NSP6 also limits autophagosome expansion regardless of how they were induced, i.e. whether they were induced directly by NSP6, or indirectly by starvation or chemical inhibition of MTOR signalling. This may favour coronavirus infection by compromising the ability of autophagosomes to deliver viral components to lysosomes for degradation [].
The transforming growth factors-beta constitute a family ofmulti-functional cytokines that regulate cell growth and differentiation []. Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide []. TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects. The protein functions as a disulphide-linked homodimer. Its sequence is characterised by the presence of several C-terminal cysteine residues, which form interlocking disulphide links arranged in a knot-like topology. A similar "cystine-knot"arrangement has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage-gated Ca2+ channels, although the precise topology differs.The three-dimensional structures of several members of the TGF-beta super-family have been deduced [, , ]. TGF-beta genes are expressed differentially, suggesting that the various TGF-beta species may have distinct physiological roles in vivo.The solution structure of human TGF-beta 1 was determined using multinuclear magnetic resonance spectroscopy with hybrid distance geometry/simulated annealing []. The structure shows a high degree of similarity to that of TGF-beta 2, but with notable differences in structure and flexibility. Examination of TGF-beta 1 mRNA levels in adult murine tissues indicates that expression is predominant in spleen, lung and placenta []. TGF-beta 1 is believed to play important roles in pathologic processes.
The breast cancer susceptibility gene contains at its C terminus two copies of a conserved domain that was named BRCT for BRCA1 C terminus. This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control [, , ]. The BRCT domain is not limited to the C-terminal of protein sequences and can be found in multiple copies or in a single copy as in RAP1 and TdT. BRCT domains are often found as tandem-repeat pairs []. Some data []indicate that the BRCT domain functions as a protein-protein interaction module.The structure of the first of the two C-terminal BRCT domains of the human DNA repair protein XRCC1 has been determined by X-ray crystallography [].Structures of the BRCA1 BRCT domains revealed a basis for a widely utilised head-to-tail BRCT-BRCT oligomerization mode []. This conserved tandem BRCT architecture facilitates formation of the canonical BRCT phospho-peptide interaction cleft at a groove between the BRCT domains. BRCT domains disrupt peptide binding by directly occluding this peptide binding groove, or by disrupting key conserved BRCT core folding determinants [].
Reoviruses are double-stranded RNA viruses that lack a membrane envelope. Their capsid is organised in two concentric icosahedral layers: an inner core and an outer capsid layer. The sigma1 protein is found in the outer capsid, and the sigma2 protein is found in the core. There are four other kinds of protein (besides sigma2) in the core, termed lambda 1-3, mu2. Interactions between sigma2 and lambda 1 and lambda 3 are thoughtto initiate core formation, followed by mu2 and lambda2 []. Sigma1 is a trimeric protein, and is positioned at the 12 vertices of the icosahedral outer capsid layer. Its N-terminal fibrous tail, arranged as a triple coiled coil,anchors it in the virion, and a C-terminal globular head interacts with thecellular receptor []. These two parts form by separate trimerization events.The N-terminal fibrous tail forms on the polysome, without the involvementof ATP or chaperones. The post- translational assembly of the C-terminalglobular head involves the chaperone activity of Hsp90, which is associatedwith phosphorylation of Hsp90 during the process []. Sigma1 protein actsas a cell attachment protein, and determines viral virulence, pathways ofspread, and tropism. Junctional adhesion molecule has been identified as areceptor for sigma1 []. In type 3 reoviruses, a small region, predicted toform a beta sheet, in the N-terminal tail was found to bind target cell surfacesialic acid (i.e. sialic acid acts as a co-receptor) and promote apoptosis [].The sigma1 protein also binds to the lambda2 core protein [].
Several 7TM receptors have been cloned but their endogenous ligands are unknown; these have been termed orphan receptors. However, recent research has identified certain pharmacological targets that could be investigated to find, for example, new potential cannabinoid receptors or channels [, , ]. GPR18 [, ], GPR55 [, ], GPR119 []show little structural similarity to CB1 and CB2 receptors, but they respond to endogenous agents analogous to the endogenous cannabinoid ligands, as well as some natural/synthetic cannabinoid receptor ligands []. However, because they do not fulfill all of the cannabinoid receptor criteria defined by IUPHAR, the classification of these proteins remains a contentious issue due to conflicting pharmacological results. As a result, they remain classified as putative endogenous agonists by IUPHAR [].This entry represents G protein-coupled receptor 18, also known as N-arachidonyl glycine receptor. It has been found to be a receptor for endogenous lipid neurotransmitters, several of which also bind to cannabinoid receptors [, , , ]. Recent research also supports the hypothesis that GPR18 is the abnormal cannabidiol receptor and N-arachidonoyl glycine, the endogenous lipid metabolite of anandamide, initiates directed microglial migration in the CNS through activation of GPR18 []. However, the pairing of GPR18 with N-arachidonoylglycine (NAGly) and tetrahydrocannabinol (THC) was not reproduced in two studies based on beta-arrestin assays [, ]. So, until further research allows a more definitive decision the function and nomenclature GPR18 is still being debated [, ].
Spectrins are involved in the support of general membrane integrity, stabilisation of cell-cell interactions, axonal growth, normal functioning of the Golgi complex and organisation of synaptic vesicles [, , ]. Spectrin is a tetrameric actin cross-linking protein, which contains two alpha and two beta subunits. Two genes for alpha-spectrin [, , ]and five for beta-spectrin have been identified in both mice and humans, each of which is alternatively spliced to produce multiple spectrin isoforms [, ]. Beta-spectrins are more diverse than alpha-spectrin, and include mammalian erythrocytic beta-spectrin, non-erythroid beta-spectrin/Fodrin (beta-G, the general form of beta-spectrin expressed in multiple tissues), a novel beta-G spectrin (ELF1-4) that lacks the C-terminal PH (pleckstrin homology) domain, the brain-specific SPTBN2, and beta-V spectrin.ELF (), a modulator of the Smad adaptor proteins involved in the TGF-beta signalling pathway, was originally identified from endodermal stem/progenitor cells committed to foregut lineage [, ]. ELF is a beta-spectrin that is important for distinct functional membrane generation, protein sorting, cell adhesion and the development of a polarized differentiated epithelial cell [, ]. ELF-deficient mice display disruption of transforming growth factor-beta (TGF-beta) signalling by Smad proteins []. Evidence from null mutants of ELF confirms that ELF is a novel beta-G spectrin and not an isoform of beta-spectrins []. Aberrations in Elf's involvement in Smad4 localization and subsequent activation of Smad4 could result in tumourigenesis.
Members of the golgin subfamily A were identified as Golgi auto-antigens []. They might be involved in maintaining cis-Golgi structure []. One of the members of this family, member 2 or GM130, is a specific interacting partner of the small GTPase Rab1b []and plays a key role in the disassembly and reassembly of the Golgi apparatus during mitosis. GM130 is also involved in vesicle tethering and fusion at the cis-cisternae to facilitate transit between transport vesicles and the stacked cisternae. It interacts with GRASPs proteins, which mediate the stacking of Golgi cisternae []. Additionally, GM130 was localised to the spindle poles and regulates microtubule organization [].Structurally, GM130 is comprised of six coiled-coil regions in the middle, a Golgi-targeting domain at the C terminus, and a p115-interacting motif at the N terminus []. This entry represents the C-terminal motif of the golgin subfamily A member 2 protein (or GM130) that is bound by the GRASP65 PDZ1 and PDZ2 domains [, ]. These interactions are required for their association and localisation of GRASP65 to the cis-cisternae.
This entry represents alpha- and gamma-type phospholipase A2 inhibitors (PLI) found in a variety of snakes, including Elapidae and Viperidae. Phospholipase A2 (PLA2; ) is a calcium-dependent enzyme that is involved in inflammatory processes such as the liberation of free arachidonic acid from the membrane pool for the biosynthesis of eicosanoids. Both Elapidae and Viperidae contain PLA2 enzymes in their venoms [, ], which can exhibit a wide variety of pharmacological effects including neurotoxicity and myotoxicity. As a result, these snakes must contain PLI in their blood in order to protect themselves from leakage of their own venom PLA2s into the circulatory system. Venomous snakes have three distinct types of PLA2-inhibitory proteins: PLI-alpha, PLI-beta, and PLI-gamma. Alpha-type PLI (PLI-alpha) proteins have been found in a number of Viperidae snakes []. Most PLI-alpha proteins are homomultimers composed of 3-5 subunits, except in Trimeresurus flavoviridis (Habu), where PLI-alpha consists of a trimer of two homologous subunits (PLI-alpha-A and PLI-alpha-B), each of which contains one C-type lectin-like domain and exhibiting significant homology to serum mannose-binding protein and lung-surfactant apoprotein []. A PLI-alpha homologue that lacks inhibitory activity was found in the non-venomous snake Elaphe quadrivirgata (Japanese four-lined ratsnake) [].Phospholipase A2 inhibitor CNF, a gamma-type PLI, inhibits the PLA2 activity of crotoxin (CTX) by replacing the acid subunit (CA) in the CTX complex []. It has a proinflammatory action through activation of important main signalling pathways for human leukocytes, in vitro []. In mice phrenic nerve-diaphragm muscle preparations it abolishes both the muscle-paralyzing and muscle-damaging activities of CTX [].
The UGA (TGA) codon is normally a termination codon, however it is also used as a selenocysteine (Sec) codon by numerous organisms []. Sec is the 21st amino acid that is inserted into selenoproteins (protein that includes a selenocysteine (Se-Cys) amino acid residue). The synthesis of Sec and its incorporation into proteins requires the activity of a number of proteins, one of which is selenophosphate synthetase (SPS), also known as the SelD gene product [, ]. SPS catalyses the production of the selenium donor compound monoselenophosphate (MSP) from selenide and ATP. MSP is then used to synthesize Sec from seryl-tRNAs []. SPS was initially identified in E. coli as the product of the gene selD, one of four essential selenoprotein synthesis genes (selA-D) [, ]. SelC is the tRNA itself, SelD acts as a donor of reduced selenium, SelA modifies a serine residue on SelC into selenocysteine, and SelB is a selenocysteine-specific translation elongation factor. 3' or 5' non-coding elements of mRNA have been found as probable structures for directing selenocysteine incorporation. This entry represents the type I SPS, mostly from bacteria.
The CorA transport system is a primary Mg2+ transporter for Bacteria and Archaea. Some members in this family may have a function other than Mg2+ transport []. Prokaryotic CorA can be classified into two sub-groups: (1) T. maritima type (group A) (2) E. coli and S.typhimurium type (group B) []. Thermotoga maritima CorA (TmCorA) has been reported to be an efflux system. It only has 2 transmembrane (TM) domains,TM1 and TM2 [, , ]. The loop connecting TM1 and TM2 contains the conserved CorA signature motifs YGMNF and MPEL. With its N- and C-terminal ends face the cytosol and its similarity to the class II CorA (a CorA group lacking the MPEL motif and may transport divalent cations out of the cell), TmCorA is predicted to be primarily involved in ion efflux []. It forms a pentameric membrane protein channel featuring a possible ion discriminating aspartate ring at the cytoplasmic entrance of the pore and two distinct cytoplasmic metal binding sites per monomer, which could have regulatory roles [, ]. E. coli and S.typhimurium CorA was predicted to have an unusual membrane topology with a relatively large N-terminal periplasmic domain (CorA-PPD) followed by a compact C-terminal domain forming three transmembrane (TM1-3) segments [, ]. However, a suggestion that TM1 is not completely transmembrane but rather peripheral to the membrane has been proposed, and in this scenario both terminalswould face the same side. A high-resolution structure from this group of proteins is needed to clarify this [].
This family is defined to identify a pair of paralogous 3' exoribonucleases in Escherichia coli, plus the set of proteins apparently orthologous to one or the other in other eubacteria. VacB was characterised originally as required for the expression of virulence genes, but is now recognised as the exoribonuclease RNase R (Rnr). Its paralog in Escherichia coli and Haemophilus influenzae is designated exoribonuclease II (Rnb). Both are involved in the degradation of mRNA, and consequently have strong pleiotropic effects that may be difficult to disentangle. Both these proteins share domain-level similarity (RNB, S1) with a considerable number of other proteins, and full-length similarity scoring below the trusted cut off to proteins associated with various phenotypes but uncertain biochemistry; it may be that these latter proteins are also 3' exoribonucleases.Competence is the ability of a cell to take up exogenous DNA from its environment, resulting in transformation. It is widespread among bacteria and is probably an important mechanism for the horizontal transfer of genes. DNA usually becomes available by the death and lysis of other cells. Competent bacteria use components of extracellular filaments called type 4 pili to create pores in their membranes and pull DNA through the pores into the cytoplasm. This process, including the development of competence and the expression of the uptake machinery, is regulated in response to cell-cell signalling and/or nutritional conditions [].
This is a cysteine-rich domain termed ADD (ATRX-DNMT3-DNMT3L, AD-DATRX) found in ATRX proteins. Chromatin-associated human protein ATRX was originally identified because mutations in the ATRX gene cause a severe form of syndromal X-linked mental retardation called ATR-X syndrome. Mutations or knockdown of ATRX expression cause diverse effects, including altered patterns of DNA methylation, a telomere-dysfunction phenotype, aberrant chromosome segregation, premature sister chromatid separation and changes in gene expression. ATRX localizes predominantly to large, tandemly repeated regions (such as telomeres, centromeres and ribosomal DNA) associated with heterochromatin, and studies show that it directs H3.3 deposition to pericentric and telomeric heterochromatin. The ADD domain of ATRX, in which most syndrome-causing mutations occur, engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. Mutations in the ATRX ADD domain cause mislocalization of ATRX protein to heterochromatin, and this may contribute to understanding the underlying etiology of ATRX syndrome. Structure analysis of the ADD domain of ATRX revealed that it contains a PHD zinc-finger domain packed against a GATA-like zinc finger. Same structure is also found in the DNMT3 DNA methyltransferases and DNMT3L [, , ].
Septin 2, alsotermed NEDD5, was originally cloned in mice. Orthologuesfrom several other species have also been identified. Micro-injection of cells with an anti-septin 2 antibody blocks cytokinesis, giving rise to binucleated cells.Septins were first discovered in budding yeast as a major component of bud neck filaments during cell septation [, ]. Later, its homologues were identified in nearly all eukaryotes, including humans. They are all GTP-binding proteins that are involved in diverse cellular functions, including cell cycle progression, vesicle trafficking, cytokinesis, cell migration, membrane dynamics, and chromosome segregation [, ]. Similar to cytoskeleton components such as actins and tubulins, they can assemble into filaments and bundles. However, unlike actin filaments and microtubules, septin filaments are not polar, similarly to intermediate filaments []. The number of septin genes per organism is variable: S. cerevisiae has seven and humans have 13 (SEPT1-12 and SEPT14; SEPT13 is a pseudogene now called SEPT7P2) []. All septins can form heteromeric complexes, which associate to form higher-order structures, including filaments, rings and cage-like formations [, ].
The MEROPS peptidase family M10, subfamily M10A, consists of extracellular metalloproteases, such as collagenase and stromelysin, that degrade the extracellular matrix and are known as matrixins or matrix metalloproteinases (MMPs). They are zinc-dependent, calcium-activated proteases synthesised as inactive precursors(zymogens), which are proteolytically cleaved to yield the active enzyme [, ].All matrixins and related proteins possess two domains: an N-terminaldomain, and a zinc-binding active site domain. The N-terminal domainpeptide, cleaved during the activation step, includes a conserved PRCGVPDVoctapeptide, known as the cysteine switch, whose Cys residue chelates theactive site zinc atom, rendering the enzyme inactive [, ]. The active enzyme degrades components of the extracellular matrix, playing a role in the initial steps of tissue remodelling during morphogenesis, wound healing, angiogenesis and tumour invasion [, ]. Although it was initially thought that the primary function of these enzymes is to degrade proteins of the extracellular matrix, MMPs have a much broader spectrum of activity that includes the proteolytic processing of cytokines, growth factors, growth factor receptors, and cell adhesion molecules [, ].
Transcription factor c-Jun (also known as transcription factor AP-1) is a member of the transcription factor activator protein (AP)-1 family, comprising Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), ATF (ATFa, ATF-2 and ATF-3) and JDP (JDP-1 and JDP-2) family members []. They are basic leucine zipper transcription factors that play a central role in regulating gene transcription in various biological processes []. c-Jun was originally identified as the normal cellular counterpart of the viral Jun oncoprotein (v-Jun) encoded by an avian sarcoma virus (ASV17). The 39kDa c-Jun protein consists of a C-terminal basic region-leucine zipper (B-ZIP) DNA-binding domain and a N-terminal transcriptional activation domain.AP-1 proteins have a α-helical bZIP domain, which contains a basic DNA-binding region and regularly spaced leucine residues known as the leucine zipper motif []. They have similar protein structure and can either form homodimers or form heterodimers with other AP-1 proteins (predominantly with Jun proteins), which can then bind to TRE-like sequences (consensus sequence 5'-TGAG/CTCA-3') []. Each of these proteins are expressed in different tissues and can be regulated in different ways, which means that every cell type has a complex mixture of AP-1 dimers with subtly different functions [].
MreB proteins are essential for cell-shape maintenance and cell morphogenesis in most non-spherical bacteria [, ]. Most rod-shaped or non-spherical bacteria possess at least one mreB homologue. In Bacillus subtilis, sidewall elongation during vegetative growth is controlled by three MreB isoforms: MreB, Mbl and MreBH []. MreB proteins are found in rod-shaped bacteria, such as E. coli and B. subtilis, that grow by dispersed intercalation of new wall material along the long axis of the cell, as opposed to those that grow from the cell pole [].The crystal structure of MreB from Thermotoga maritima was resolved using X-ray crystallography, and the results suggested that MreB proteins form long filaments that wrap around the long axis of the cell close to the cell membrane, forming helix-like structures. These observations led to the idea that MreB proteins might have an actin-like cytoskeletal role in bacteria [, ]. However, this remains controversial [, ]. MreB and MreB-like proteins are thought to act as scaffolds, guiding the localization and activity of key peptidoglycan synthesizing proteins during cell elongation [, ]. MreB has also been implicated in chromosome segregation [].
Proteins in this family contain an N-terminal BTB domain and the C-terminal Kelch motifs. The BTB/POZ domain facilitates protein binding. The Kelch motif is a 50-residue motif named after the Drosophila mutant in which it was first identified []. This sequence motif represents one β-sheet blade, and several of these repeats can associate to form a β-propeller. Some members in this family also contain a BACK domain, which is a conserved 130-residue region between the BTB domain and Kelch motifs[]. BTB-kelch protein family includes KLHL and part of the KBTBD subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains.KBTBD subfamily typically possess a BTB and BACK domain and two to four Kelch motifs []. It's worth noting that not all the KBTBD subfamily members are in this entry. KLHL subfamily members generally have a BTB/POZ domain, a BACK domain, and five to six Kelch motifs []. Gigaxonin is one of the KLHL subfamily members. It binds to the ubiquitin-activating enzyme E1 through its N-terminal BTB domain and its six C-terminal kelch repeat domain interacts directly with the light chain (LC) of microtubule-associated protein 1B (MAP1B) [, ].
This family consists of several Cbb3-type cytochrome oxidase components (FixQ/CcoQ). FixQ is found in nitrogen fixing bacteria. Since nitrogen fixation is an energy-consuming process, effective symbioses depend on operation of a respiratory chain with a high affinity for O2, closely coupled to ATP production. This requirement is fulfilled by a special three-subunit terminal oxidase (cytochrome terminal oxidase cbb3), which was first identified in Bradyrhizobium japonicum as the product of the fixNOQP operon [].Cytochrome cbb3 oxidase, the terminal oxidase in the respiratory chains of proteobacteria, is a multi-chain transmembrane protein located in the cell membrane. Like other cytochrome oxidases, it catalyses the reduction of O2 and simultaneously pumps protons across the membrane. Found exclusively in proteobacteria, cbb3 is believed to be a modern enzyme that has evolved independently to perform a specialized function in microaerobic energy metabolism [, , ]. The cbb3 operon contains four genes (ccoNOQP or fixNOQP), with ccoN coding for subunit I []. Instead of a CuA-containing subunit II analogous to other cytochrome oxidases, cbb3 utilizes subunits ccoO and ccoP, which contain one and two hemes, respectively, to transfer electrons to the binuclear centre. ccoQ, the fourth subunit, is a single transmembrane helix protein. It has been shown to protect the core complex from proteolytic degradation by serine proteases [].
This entry represents the regulator of ribonuclease E activity A (RraA). These proteins contain a swivelling 3-layer beta/beta/alpha domain that appears to be mobile in most multi-domain proteins known to contain it. These proteins are structurally similar, and may have distant homology, to the phosphohistidine domain of pyruvate phosphate dikinase. The RraA fold is an ancient platform that has been adapted for a wide range of functions. RraA had been identified as a putative demethylmenaquinone methyltransferase and was annotated as MenG, but further analysis showed that RraA lacked the structural motifs usually required for methylases []. The Escherichia coli protein regulator RraA acts as a trans-acting modulator of RNA turnover, binding essential endonuclease RNase E and inhibiting RNA processing []. RNase E forms the core of a large RNA-catalysis machine termed the degradosomes. RraA (and RraB) causes remodelling of degradosome composition, which is associated with alterations in RNA decay and global transcript abundance and as such is a bacterial mechanism for the regulation of RNA cleavage.This fold is also found in 4-hydroxy-4-methyl-2-oxoglutarate aldolase, also known as RraA-like protein []and at the C terminus of the DlpA protein .
The TCP-1 protein [, ](Tailless Complex Polypeptide 1) was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different subunits. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins.The CCT subunits are highly related to archaebacterial counterparts:TF55 and TF56 [], a molecular chaperone from Sulfolobus shibatae. TF55 has ATPase activity, is known to bind unfolded polypeptides and forms a oligomeric complex of two stacked nine-membered rings.Thermosome [], from Thermoplasma acidophilum. The thermosome is composed of two subunits (alpha and beta) and also seems to be a chaperone with ATPase activity. It forms an oligomeric complex of eight-membered rings.The TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).
The frizzled (fz) domain is an extracellular domain of about 120 amino acids.It was first identified in the alpha-1 chain of type XVIII collagen and in members of the Frizzled family of seven transmembrane (7TM) proteins which act as receptors for secreted Wingless (Wg)/Wnt glycoproteins []. In addition to these proteins, one or two copies of the fz domain are also found [, , , , ]in:The Frzb family; secreted frizzled-like proteins.Smoothened; another 7TM receptor involved in hedgehog signaling.Carboxpeptidase Z (CPZ).Transmembrane serine protease corin (atrial natriuretic peptide-converting enzyme).Two receptor tyrosine kinases (RTKs) subfamilies, the Ror family and the muscle-specific kinase (MuSK) family.As the fz domain contains 10 cysteines which are largely conserved, it has also been called cysteine-rich domain (CRD) []. The fz domain also contains several other highly conserved residues, for example, a basic amino acid follows C6, and a conserved proline residues lies four residues C-terminal to C9 []. The crystal structure of a fz domain shows that it is predominantly α-helical with all cysteines forming disulphide bonds. In addition to helical regions, two short β-strands at the N terminus form a minimal β-sheet with the second beta sheet passing through a knot created by disulphide bonds [].Several fz domains have been shown to be both necessary and sufficient for Wg/Wnt ligand binding, strongly suggesting that the fz domain is a Wg/Wnt interacting domain [, ].
This group belongs to the ferritin domain superfamily and has the ferritin-like structural fold. Ferritins constitute a broad superfamily of iron storage proteins, widespread in all domains of life [, ]. Ferritins and bacterioferritins have essentially the same architecture, assembling in a 24mer cluster to form a hollow, roughly spherical, construction. This consists of a mineral core of hydrated ferric oxide and a multi-subunit protein shell, which encloses the former and assures its solubility in an aqueous environment. Due to the absence of the C-terminal fifth helix of 24mer ferritins, members of the Dps group assemble only to dodecameric protein shells [].Members of this entry were originally discovered as stress proteins, which protect DNA against oxidative stress during nutrient starvation [], hence the name Dps (DNA protection during starvation protein). Several members of the group, such as Dps from Escherichia coli or the Dps homologue from Bacillus subtilis, exhibit a DNA-binding activity that is at least partially linked with iron complexation []. DNA binding by these proteins was shown to suffice for protection against oxidative DNA damage and might be mediated by magnesium ions, which bridge the protein surfaces with the polyanionic DNA [, ]. Functionally, this group is much more diverse, with many members promoting iron incorporation, while others act as immunogens, neutrophil activators [], cold-shock proteins, or constituents of fine-tangled pili []. Another mode of protection against reactive oxygen species implies the preferential consumption of hydrogen peroxide instead of oxygen during biomineralization [].For additional information please see [, ].
This group belongs to the ferritin domain superfamily and has the ferritin-like structural fold. Ferritins constitute a broad superfamily of iron storage proteins, widespread in all domains of life [, ]. Ferritins and bacterioferritins have essentially the same architecture, assembling in a 24mer cluster to form a hollow, roughly spherical, construction. This consists of a mineral core of hydrated ferric oxide and a multi-subunit protein shell, which encloses the former and assures its solubility in an aqueous environment. Due to the absence of the C-terminal fifth helix of 24mer ferritins, members of the Dps group assemble only to dodecameric protein shells [].Members of this entry were originally discovered as stress proteins, which protect DNA against oxidative stress during nutrient starvation [], hence the name Dps (DNA protection during starvation protein). Several members of the group, such as Dps from Escherichia coli, exhibit a DNA-binding activity that is at least partially linked with iron complexation []. DNA binding by these proteins was shown to suffice for protection against oxidative DNA damage and might be mediated by magnesium ions, which bridge the protein surfaces with the polyanionic DNA [, ]. Dps also contributes to defense against copper stress in growing cells of E. coli [].
Inhibitor of growth protein 3 (ING3) is a member of the ING family of tumour suppressors that regulate cell cycle progression, apoptosis and DNA repair []. ING3 is a component of the NuA4 histone acetyltransferase complex []and the SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AFZ from the nucleosome []. ING3 contains an N-terminal ING domain and a C-terminal plant homeodomain (PHD) finger.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
DNA carries the biological information that instructs cells how to existin an ordered fashion: accurate replication is thus one of the mostimportant events in the cell life cycle. This function is mediated byDNA-directed DNA-polymerases, which add nucleotide triphosphate (dNTP)residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers forchain elongation, although terminal proteins may also be used. Three motifs, A, B and C [], are seen to be conserved across all DNA-polymerases, with motifs A and C also seen in RNA- polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (Escherichia coli) structure: motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].DNA polymerases () can be classified, on the basis of sequencesimilarity [, ], into at least four different groups: A, B, C and X. Members of family X are small (about 40kDa) compared with other polymerases and encompass two distinct polymerase enzymes that have similar functionality: vertebrate polymerase beta (same as yeast pol 4), and terminal deoxynucleotidyl-transferase (TdT) (). The former functions in DNA repair, whilethe latter terminally adds single nucleotides to polydeoxynucleotide chains.Both enzymes catalyse addition of nucleotides in a distributive manner, i.e. theydissociate from the template-primer after addition of each nucleotide.DNA-polymerases show a degree of structural similarity with RNA-polymerases.
Mortality factor 4-like protein 1 (MORF4L1 or MRG15) is a transcription factor and a chromodomain protein. It is a component of the NuA4 histone acetyltransferase complex [], the Sin3 complex which acts to repress transcription by deacetylation of nucleosomal histones [], and the nuclear protein complexes MAF1 and MAF2 []. MRG15 also interacts with the BRCA complex, especially with subunit PALB2 []. MRG15 has an MRG domain in its C-terminal region, which interacts with the nucleoprotein PAM14 during transcriptional regulation [].The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
Mortality factor 4-like protein 2 (MORF4L2 or MRGX) is a component of the NuA4 histone acetyltransferase complex []and the MSIN3A complex which acts to repress transcription by deacetylation of nucleosomal histones []. MRGX interacts with MRFAP1 and RB1 and represses the B-myb promoter in EJ cells but activates it in HeLa cells []. MRGX contains an MRG domain.The NuA4 histone acetyltransferase complex (also known as the TRRAP/TIP60-containing histone acetyltransferase complex) acetylates nucleosomal histones H4 and H2A thereby activating selected genes for transcription and is a a key regulator of transcription, cellular response to DNA damage and cell cycle control []. In yeast, where the complex was first identified, NuA4 consists of at least ACT1, ARP4, YAF9, VID21, SWC4, EAF3, EAF5, EAF6, EAF7, EPL1, ESA1, TRA1 and YNG2 []. In humans, the complex is composed of the histone acetyltransferase KAT5 (also known as TIP60) plus the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, MAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 [].
The T-box gene family is an ancient group of putative transcription factors that appear to play a critical role in the development of all animal species.These genes were uncovered on the basis of similarity to the DNA binding domain []of murine Brachyury (T) gene product, which similarity is the defining feature of the family. The Brachyury gene is named for its phenotype, which was identified 70 years ago as a mutant mouse strain with a short blunted tail. The gene, and its paralogues, have become a well-studied model for the family, and hence much of what is known about the T-box family is derived from the murine Brachyury gene.Consistent with its nuclear location, Brachyury protein has a sequence-specific DNA-binding activity and can act as atranscriptional regulator []. Homozygous mutants for the gene undergo extensive developmental anomalies, thus rendering the mutation lethal []. The postulated role of Brachyury is as a transcription factor, regulating the specification and differentiation of posterior mesoderm during gastrulation in a dose-dependent manner [].Common features shared by T-box family members are, DNA-binding and transcriptional regulatory activity, a role in development and conserved expression patterns, most of the known genes in all species being expressed in mesoderm of mesoderm precursors []. Members of the T-box family contain a domain of about 170 to 190 amino acids known as the T-box domain [, , ]and which probably binds DNA.
This superfamily represents a RNA-binding domain identified when studying Tudor domain containing proteins and was designed LOTUS after Limkain, Oskar and TUdor-containing proteins 5 and 7.This predicted RNA-binding domain found in insect Oskar and vertebrate TDRD5/TDRD7 proteins that nucleate or organise structurally related ribonucleoprotein (RNP) complexes, the polar granule and nuage, is poorly understood [, ]. The domain adopts the winged helix-turn-helix fold and binds RNA with a potential specificity for dsRNA []. In eukaryotes, this domain is often combined in the same polypeptide with protein-protein- or lipid- interaction domains that might play a role in anchoring these proteins to specific cytoskeletal structures. Thus, proteins with this domain might have a key role in the recognition and localisation of dsRNA, including miRNAs, rasiRNAs and piRNAs hybridized to their targets. In other cases, this domain is fused to ubiquitin-binding, E3 ligase and ubiquitin-like domains, indicating a previously under-appreciated role for ubiquitination in regulating the assembly and stability of nuage-like RNP complexes. Both bacteria and eukaryotes encode a conserved family of proteins that combines this predicted RNA-binding domain with a previously uncharacterised RNAse domain belonging to the superfamily that includes the 5'->3' nucleases, PIN and NYN domains [].
Lon protease belongs to the S16 peptidase family and is an ATP-dependent serine protease that mediates the selective degradation of mutant and abnormal proteins, as well as certain short-lived regulatory proteins. It is required for cellular homeostasis and for survival from DNA damage and developmental changes induced by stress []. In pathogenic bacteria, it is required for the expression of virulence genes that promote cell infection [].Lon (La) protease was the first ATP-dependent protease to be purified fromE. coli [, , , ]. The enzyme is a homotetramer of 87kDa subunits, with one proteolytic and one ATP-binding site per monomer, making it structurally less complex than other known ATP-dependent proteases []. Despite this relative structural simplicity, Lon recognises its substrates directly, without delegating the task of substrate recognition to other enzymes []. This signature defines the bacterial and eukaryotic lon proteases. This family of sequences does not include the archaeal lon homologues, . In the eukaryotes the majority of the proteins are located in the mitochondrial matrix [, ]. The yeast homologue, Pim1, is required for mitochondrial function and is constitutively expressed, but is increased after thermal stress, suggesting that Pim1 may play a role in the heat shock response [].
Solute carrier family 12 member 3 (Slc12a3) is also known as Tsc (thiazide-sensitive Na-Cl co-transporter). Tsc is a large integral membraneprotein (~1000 amino acids) that mediates the coupled transport of Na+andCl-in an electrically silent manner. In the mammalian kidney, it is thedominant mechanism mediating Cl-absorption in the early distal tubule, andhere it is the target of the widely-used thiazide class of diuretic drugs.It is also known to be present in the urinary bladder of the winterflounder (Pseudopleuronectes americanus), from where the gene encoding it was initially cloned [].Hydrophobicity analysis predicts the Na-Cl co-transporter to have 12transmembrane (TM) domains and comparisons with other cloned ionco-transporters reveals that a superfamily of electroneutral cation-chlorideco-transporters exists, which includes the K-Cl co-transporters ()and the Na-K-Cl co-transporters (). All share a similar predictedmembrane topology in a central hydrophobic domain, together withhydrophilic N- and C-termini that are likely cytoplasmic [].Mutations in the thiazide-sensitive Na-Cl co-transporter have beenfound that give rise to Gitelman's variant of Bartter's syndrome,an inherited kidney disease characterised by hypokalaemic alkalosis [].
Gap junction alpha-3 protein (also called connexin46, or Cx46) is a connexinof ~415 amino acid residues. The bovine form is slightly shorter (401residues) and is hence known as Cx44, having a molecular mass of ~44 kD.Cx46 (together with Cx50) is a connexin isoform expressed in the lens fibresof the eye. Here, gap junctions join the cells into a functional syncytium,and also couple the fibres to the epithelial cells on the anterior surfaceof the lens. The lens fibres depend on this epithelium for their metabolicsupport, since they lose their intra-cellular organelles, and accumulatehigh concentrations of crystallins, in order to produce their opticaltransparency. Genetically-engineered mice deficient in Cx46 demonstrate theimportance of Cx46 in forming lens fibre gap junctions; these mice developnormal lenses, but subsequently develop early onset senile-type cataractsthat resemble human nuclear cataracts. Aberrant proteolysis of crystallin proteins was observed in the lenses of Cx46-null mice []. A Cx46 mutant in a highly conserved threonine has been linked toautosomal dominant cataracts. This mutation causes loss of gap junction function and alters hemi-channel gating [].
This entry represents the redox inactive TRX-like domain b' found at the C terminus of vertebrate nucleoredoxins (NRX). Despite its name, nucleoredoxins is localized in both the cytosol and the nucleus []. It interacts with phosphofructokinase 1 and protein phosphatase 2A [, ]. It may be involved in transcriptional regulation []and has been shown to negatively regulate Wnt-beta-catenin signalling and binds to Dvl (Dishevelled) in a redox-dependent manner []. The mouse NRX gene is implicated in streptozotocin-induced diabetes []. The NRX protein contains three TRX domains organized in a structure similar to those of PDIs that contain three to four TRX domains. The N- and C-terminal domains of NRX share a high similarity to the b' domains of PDIs and lack a redox active centre. The central domain, however, contains the dithiol active site motif Cys-Pro-Pro-Cys and was shown to be active in the insulin reduction assay. The function of the PDI-like domains in NRX is unclear; they may be important for substrate recognition [].Thioredoxin family members are evolutionary conserved proteins that possess catalytically active cysteine residues that can reduce the disulphide bonds of target proteins. Thioredoxin family members include nucleoredoxins (NRX), Trxs, glutaredoxins (Grxs), peroxiredoxins (Prxs), and protein disulfide isomerases (PDIs) that catalyze cellular redox signaling []. Thioredoxin possesses a conserved WCGPC (Trp-Cys-Gly-Pro-Cys) motif, and the two cysteine residues (Cys32 and Cys35 in human TRX1) are directly involved in oxidoreductase reactivity [].
This entry includes Rap2a/b/c, which is part of the Rap subfamily of the Ras family. Both isoform 3 of the human mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Traf2- and Nck-interacting kinase (TNIK) are putative effectors of Rap2 in mediating the activation of c-Jun N-terminal kinase (JNK) to regulate the actin cytoskeleton [, ]. In human platelets, Rap2 was shown to interact with the cytoskeleton by binding the actin filaments []. In embryonic Xenopus development, Rap2 is necessary for the Wnt/beta-catenin signaling pathway []. The Rap2 interacting protein 9 (RPIP9) is highly expressed in human breast carcinomas and correlates with a poor prognosis, suggesting a role for Rap2 in breast cancer oncogenesis []. Rap2b, but not Rap2a, Rap2c, Rap1a, or Rap1b, is expressed in human red blood cells, where it is believed to be involved in vesiculation []. A number of additional effector proteins for Rap2 have been identified, including the RalGEFs RalGDS, RGL, and Rlf, which also interact with Rap1 and Ras [].Most Ras proteins contain a lipid modification site at the C terminus, with a typical sequence motif CaaX, where a = an aliphatic amino acid and X = any amino acid. Lipid binding is essential for membrane attachment, a key feature of most Ras proteins [].
HAUS4 contributes to mitotic spindle assembly, maintenance of centrosome integrity and completion of cytokinesis as part of the HAUS augmin-like complex [, ].Assembly of a robust microtubule-based mitotic spindle is essential for accurate segregation of chromosomes to progeny. Spindle assembly relies on the concerted action of centrosomes, spindle microtubules, molecular motors and non-motor spindle proteins. A number of novel regulators of spindle assembly have been identified: one of these is HAUS, an 8-subunit protein complex that shares similarity with Drosophila Augmin [, ].HAUS localises to interphase centrosomes and to mitotic spindle micro- tubules; its disruption induces microtubule-dependent fragmentation of centrosomes, and an increase in centrosome size. HAUS disruption results in the destabilisation of kinetochore microtubules and eventual formation of multipolar spindles. Such severe mitotic defects are alleviated by co-depletion of NuMA, indicating that both factors regulate opposing activities. HAUS disruption alters NuMA localisation, suggesting that mis-localised NuMA activity contributes to the observed spindle and centrosome defects. The Augmin complex (HAUS) is thus a critical, evolutionarily conserved multi-subunit protein complex that regulates centrosome and spindle integrity [].The HAUS (Homologous to AUgmin Subunits) individual subunits have been designated HAUS1 to HAUS8 []. The HAUS augmin-like complex subunit 4 was previously known as C14orf94.
Rab20 is one of several Rab proteins that appear to be restricted in expression to the apical domain of murine polarized epithelial cells. It is expressed on the apical side of polarized kidney tubule and intestinal epithelial cells, and in non-polarized cells. It also localizes to vesico-tubular structures below the apical brush border of renal proximal tubule cells and in the apical region of duodenal epithelial cells. Rab20 has also been shown to colocalize with vacuolar H+-ATPases (V-ATPases) in mouse kidney cells, suggesting a role in the regulation of V-ATPase traffic in specific portions of the nephron []. It was also shown to be one of several proteins whose expression is upregulated in human myelodysplastic syndrome (MDS) patients [].Rabs are regulated by GTPase activating proteins (GAPs), which interact with GTP-bound Rab and accelerate the hydrolysis of GTP to GDP. Guanine nucleotide exchange factors (GEFs) interact with GDP-bound Rabs to promote the formation of the GTP-bound state. Rabs are further regulated by guanine nucleotide dissociation inhibitors (GDIs), which facilitate Rab recycling by masking C-terminal lipid binding and promoting cytosolic localization. Most Rab GTPases contain a lipid modification site at the C terminus, with sequence motifs CC, CXC, or CCX. Lipid binding is essential for membrane attachment, a key feature of most Rab proteins [, ].
Flavin-containing monooxygenases (FMOs) constitute a family of xenobiotic-metabolising enzymes []. Using an NADPH cofactor and FAD prosthetic group, these microsomal proteins catalyse the oxygenation of nucleophilic nitrogen, sulphur, phosphorus and selenium atoms in a range of structurally diverse compounds. FMOs have been implicated in the metabolism of a number of pharmaceuticals, pesticides and toxicants. In man, lack of hepatic FMO-catalysed trimethylamine metabolism results in trimethylaminuria (fish odour syndrome). Five mammalian forms of FMO are now known and have been designated FMO1-FMO5 [, ,, , ]. This is a recent nomenclature based on comparison of amino acid sequences, and has been introduced in an attempt to eliminate confusion inherent in multiple, laboratory-specific designations and tissue-based classifications []. Following the determination of the complete nucleotide sequence of Saccharomyces cerevisiae (Baker's yeast) [], a novel gene was found to encode a protein with similarity to mammalian monooygenases. In Aspergillus, flavin-containing monooxygenases ustF1 and ustF2 are components in the biosynthesis of the antimitotic tetrapeptide ustiloxin B, a secondary metabolite. The monooxygenases modify the side chain of the intermediate S-deoxyustiloxin H [].
This entry includes SKP1 from yeasts, animals and plants. Mammlian S-phase kinase-associated protein 1 (SKP1) is an essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription []. It is also part of the ubiquitin E3 ligase complex (Skp1-Pam-Fbxo45) that controls the core epithelial-to-mesenchymal transition-inducing transcription factors [].Budding yeast Skp1 is a kinetochore protein found in several complexes, including the SCF ubiquitin ligase complex, the CBF3 complex that binds centromeric DNA [], and the RAVE complex that regulates assembly of the V-ATPase []. In Dictyostelium discoideum (Slime mold) FP21 was shown to be glycosylated in the cytosol and has homology to SKP1 [].Arabidopsis Skp1 is part of the Skp1/Cullin1/F-box protein COI1 (SCFCOI1) E3 ubiquitin ligase complex required for vegetative and floral organ development as well as for male gametogenesis [, ]. 21 Skp1-related genes, called Arabidopsis-SKP1-like (ASK), have been uncovered in the Arabidopsis genome. They may collectively perform a range of functions and may regulate different developmental and physiological processes [, ].
Preferentially expressed antigen of melanoma (PRAME) was first isolated as a human melanoma antigen by cDNA expression cloning using melanoma-reactive cytotoxic Tcells (CTL). PRAME is a tumor associated antigen (TAA) of particular interest since it is widely expressed by lymphoid and myeloid malignancies and solid tumors, including melanomas, sarcomas, head and neck cancers, small-cell lung carcinomas and renal cell cancers. In normal tissues, PRAME expression has been reported in testis and low levels are found in endometrium, ovaries and adrenals [, , , ]. However, the PRAME gene is also expressed, although at a lower intensity, in CD34+ stem cells from healthy donors, which might constitute a problem for its application as a target in tumor immunotherapy []. Epigenetic events represent the main mechanism regulating the expression of PRAME including DNA methylation of several promoter regions [, ]. Members of the PRAME gene family encode leucine-rich repeat (LRR) proteins functioning as transcription regulators in cancer cells, and are thought to possess roles in spermatogenesis and oogenesis [, ].
DNA carries the biological information that instructs cells how to exist in an ordered fashion. Accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. DNA-dependent DNA polymerases have been grouped into families, denoted A, B and X, on the basis of sequence similarities [, ]. Members of family A, which includes bacterial and bacteriophage polymerases, share significant similarity to Escherichia coli polymerase I; hence family A is also known as the pol I family. The bacterial polymerases also contain an exonuclease activity, which is coded for in the N-terminal portion. Three motifs, A, B and C [], are seen to be conserved across all DNA polymerases, with motifs A and C also seen in RNA polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (E. coli) structure. Motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].This entry represents the DNA-polymerase A family.
DNA carries the biological information that instructs cells how to exist in an ordered fashion. Accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA moleculesare generally used as primers for chain elongation, although terminal proteins may also be used. DNA-dependent DNA polymerases have been grouped into families, denoted A, B and X, on the basis of sequence similarities [, ]. Members of family A, which includes bacterial and bacteriophage polymerases, share significant similarity to Escherichia coli polymerase I; hence family A is also known as the pol I family. The bacterial polymerases also contain an exonuclease activity, which is coded for in the N-terminal portion. Three motifs, A, B and C [], are seen to be conserved across all DNA polymerases, with motifs A and C also seen in RNA polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (E. coli) structure. Motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].
This entry represents flap endonucleases from eukaryotes, bacteria, viruses and archaea. Flap endonucleases (FENs) catalyse the exonucleolytic hydrolysis of blunt-ended duplex DNA substrates and the endonucleolytic cleavage of 5'-bifurcated nucleic acids at the junction formed between single and double-stranded DNA [].In prokaryotes, the essential FEN reaction can be performed by the N-terminal 5'-3' exonuclease domain present on DNA polymerase I. Some eubacteria, however, possess a second gene encoding a 5'-3' exonuclease domain [, ]. Two distinct classes of these independent bacterial FENs exist: Xni (ExoIXI) from Escherichia coli and SaFEN (Staphylococcus aureus FEN). SaFEN has both FEN and 5'-3' exonuclease activities. Xni (ExoIX) was previously identified as a 3'-5'exonuclease and named exonuclease IX (exonuclease 9) [, ]but subsequently found to possess flap endonuclease activity, but not exonuclease activity [, , ].Archaea, eukaryotes, bacteriophages and some viruses encode a separate FEN enzyme but lack FEN domains on their DNA polymerases []. Escherichia phage T5 encodes the flap endonuclease D15, which catalyzes both the 5'-exonucleolytic and structure-specific endonucleolytic hydrolysis of DNA branched nucleic acid molecules [, , ]. In bacteriophage T4, disruption of the rnh gene (which encodes a FEN, known historically as T4 RNase H) results in slower, less accurate DNA replication. Bacteriophage T4 has both 5' nuclease and flap endonuclease activities [].
FRS2 (also called Suc1-associated neurotrophic factor (SNT)-induced tyrosine-phosphorylated target) proteins are membrane-anchored adaptor proteins. They are composed of an N-terminal myristoylation site followed by a phosphotyrosine binding (PTB) domain, which has a PH-like fold, and a C-terminal effector domain containing multiple tyrosine and serine/threonine phosphorylation site. The FRS2/SNT proteins show increased tyrosine phosphorylation by activated receptors, such as fibroblast growth factor receptor (FGFR) and TrkA, recruit SH2 domain containing proteins such as Grb2, and mediate signals from activated receptors to a variety of downstream pathways. The PTB domains of the SNT proteins directly interact with the canonical NPXpY motif of TrkA in a phosphorylation dependent manner, they directly bind to the juxtamembrane region of FGFR in a phosphorylation-independent manner [, ]. This domain can also be found in FRS3 []. PTB domains have a common PH-like fold and are found in various eukaryotic signaling molecules. This domain was initially shown to binds peptides with a NPXY motif with differing requirements for phosphorylation of the tyrosine, although more recent studies have found that some types of PTB domains can bind to peptides lacking tyrosine residues altogether. In contrast to SH2 domains, which recognize phosphotyrosine and adjacent carboxy-terminal residues, PTB-domain binding specificity is conferred by residues amino-terminal to the phosphotyrosine. PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains. This domain is part of the IRS-like subgroup [, ].
Seeds of cereals contain a variety of serine protease and alpha-amylase inhibitors. These inhibitors can be grouped into families based on structural similarities. Rice seed allergenic proteins (RA) have sequence homology to seed trypsin/alpha-amylase inhibitors. Some have serine peptidase activity or alpha-amylase, and a few are bifunctional. The proteins contain ~10 cysteine residues, all of which are involved in disulphide bond formation [].This majority of sequences in this family are from Oryza sativa (Rice), exceptions are from Hordeum vulgare (Barley) and Triticum aestivum (Wheat). The majority are annotated either as alpha-amylase inhibitors or seed allergens and all belong to the MEROPS inhibitor family I6, clan IJ. There is no direct evidence to suggest that they can inhibit serine peptidases belonging to MEROPS peptidase S1 [], and studies on a closely related alpha-amylase inhibitor from Secale cereale (Rye) demonstrates no activity against trypsin, and illustrates the necessity of exercising caution in assigning function based on sequence comparisons [].The rice seed allergenic proteins are encoded by a multigene family consisting of at least four members. A conserved sequence similar to a motif identified in rice glutelin promoters was observed in the 5' regionof the two genes. RA genes are specifically expressed in ripening seeds and they accumulate maximally 15-20 days after flowering [].
The class III basic helix-turn-helix (bHLH) transcription factors have proliferative and apoptotic roles and are characterised by the presence of a leucine zipper adjacent to the bHLH domain. The myc oncogene was first discovered in small-cell lung cancer cell lines where it is found to be deregulated []. The Myc protein contains an N-terminal transcriptional regulatory domain followed by a nuclear localization signal and a C-terminal basic DNA binding domain tethered to a helix-loop-helix-leucine zipper (HLH-Zip) dimerization motif. Myc forms a heterodimer with Max, and this complex regulates cell growth through direct activation of genes involved in cell replication [, , ].The `leucine zipper' is a structure that is believed to mediate the function of several eukaryotic gene regulatory proteins. The zipper consists of a periodic repetition of leucine residues at every seventh position, and regions containing them appear to span eight turns of α-helix. The leucine side chains that extend from one helix interact with those from a similar helix, hence facilitating dimerisation in the form of a coiled-coil. Leucine zippers are present in many gene regulatory proteins, including the CREB proteins, Jun/AP1 transcription factors, fos oncogene and fos-related proteins, C-myc, L-myc and N-myc oncogenes, and so on.
MADS genes in plants encode key developmental regulators of vegetative and reproductive development. The majority of the plant MADS proteins share a stereotypical MIKC structure. It comprises (from N- to C-terminal) an N-terminal domain, which is, however, present only in a minority of proteins; a MADS domain (see , ), which is the major determinant of DNA-binding but which also performs dimerisation and accessory factor binding functions; a weakly conserved intervening (I) domain, which constitutes a key molecular determinant for the selective formation of DNA-binding dimers; a keratin-like (K-box) domain, which promotes protein dimerisation; and a C-terminal (C) domain, which is involved in transcriptional activation or in the formation of ternary or quaternary protein complexes. The 80-amino acid K-box domain was originally identified as a region with low but significant similarity to a region of keratin, which is part of the coiled-coil sequence constituting the central rod-shaped domain of keratin [, , ].The K-box protein-protein interaction domain which mediates heterodimerization of MIKC-type MADS proteins contains several heptad repeats in which the first and the fourth positions are occupied by hydrophobic amino acids suggesting that the K-box domain forms three amphipathic α-helices referred to as K1, K2, and K3 [].
Nucleotide excision repair (NER) is a conserved DNA repair pathway that enables the repair of chemically and structurally distinct DNA lesions. In prokaryotes, the UvrA, UvrB and UvrC proteins mediate NER in a multistep, ATP-dependent reaction. UvrC catalyses the first incision on the fourth or fifth phosphodiester bond 3' and on the eighth phosphodiester bond 5' from the damage that is to be excised. UvrC proteins contain conserved regions: the GIY-YIG domain, the cys-rich region, the UvrBC domain which interacts with uvrB, the RNAse H endonuclease domain and the Helix hairpin Helix (HhH)2 domain [].This entry represents the RNAse H endonuclease domain, located at the C-terminal, between the UvrBC and the (HhH)2 domains, nearby the N-terminal of the HhH. Despite the lack of sequence homology, the endonuclease domain has an RNase H-like fold, which is characteristic of enzymes with nuclease or polynucleotide transferase activities. RNase H-related enzymes typically contain a highly conserved carboxylate triad, usually DDE, in their catalytic centre. However, instead of a third carboxylate, UvrC of Thermotoga maritima was found to contain a highly conserved histidine (H488) on helix-4 in close proximity to two aspartates [].
This entry includes Tpt1 and its homologues from all domains of life. Tpt1 was first discovered as an essential component of the fungal tRNA splicing pathway, which characteristically generates a 2'-PO4, 3'-5' phosphodiester splice junction during the tRNA ligation reaction []. It is an enzyme that catalyzes the transfer of an internal RNA 2'-monophosphate (2'-PO4) to NAD+ to form a 2'-OH RNA, ADP-ribose 1"-2"cyclic phosphate, and nicotinamide []. Interestingly, many Tpt1 homologues have no obvious need for an RNA 2'-phosphotransferase because: (i) they lack tRNA introns; and/or (ii) they are not known to have an enzymatic pathway that generates 2'-PO4, 3'-5' phosphodiester RNA structures. There are more evidence showing that Tpt1 homologues are not limited to the canonical activity of Tpt1 healing the 2'-PO4, 3'-5' phosphodiester RNA splice junction formed during fungal and plant tRNA splicing []. Instead, the ADP-ribosyl transfer to a phosphorylated substrate is the unifying mechanistic feature of Tpt1-catalyzed reactions. For instance, some Tpt1 homologues have been shown to catalyze the transfer of ADP-ribose from NAD+ to a 5'-monophosphate end of RNA or DNA to install a 5'-phospho-ADP-ribose cap structure [].
Formylmethanofuran:tetrahyromethanopterin formyltransferase (Ftr) is involved in C1 metabolism in methanogenic archaea, sulphate-reducing archaea and methylotrophic bacteria. It catalyses the following reversible reaction:N-formylmethanofuran + 5,6,7,8-tetrahydromethanopterin = methanofuran + 5-formyl-5,6,7,8-tetrahydromethanopterinFtr from the thermophilic methanogen Methanopyrus kandleri (optimum growth temperature 98 degrees C) is a hyperthermophilic enzyme that is absolutely dependent on the presence of lyotropic salts for activity and thermostability. The crystal structure of Ftr, determined to a reveals a homotetramer composed essentially of two dimers. Each subunit is subdivided into two tightly associated lobes both consisting of a predominantly antiparallel beta sheet flanked by alpha helices forming an alpha/beta sandwich structure. The approximate location of the active site was detected in a region close to the dimer interface []. Ftr from the mesophilic methanogen Methanosarcina barkeri and the sulphate-reducing archaeon Archaeoglobus fulgidus have a similar structure [].In the methylotrophic bacterium Methylobacterium extorquens, Ftr interacts with three other polypeptides to form an Ftr/cyclohydrolase complex which catalyses the hydrolysis of formyl-tetrahydromethanopterin to formate during growth on C1 substrates [].This entry represents the ferredoxin-like Ftr C-terminal domain.
LEA (late embryogenesis abundant) proteins were first identified in land plants. Plant LEA proteins have been found to accumulate to high levels during the last stage of seed formation (when a natural desiccation of the seed tissues takes place) and during periods of water deficit in vegetative organs. Later, LEA homologues have also been found in various species [, ]. They have been classified into several subgroups in Pfam and according to Bray and Dure [].Dehydrin has been classified as part of the LEA family (D-11 from Dure, or group 2 from Bray) []. Dehydrins contribute to freezing stress tolerance in plants and it was suggested that this could be partly due to their protective effect on membranes [].Dehydrins share a number of structural features. One of the most notablefeatures is the presence, in their central region, of a continuous run offive to nine serines followed by a cluster of charged residues. Such a regionhas been found in all known dehydrins so far with the exception of peadehydrins. A second conserved feature is the presence of two copies of alysine-rich octapeptide; the first copy is located just after the clusterof charged residues that follows the poly-serine region and the second copyis found at the C-terminal extremity.
This entry represents the tubulin-like proteins FtsZ and CetZ. FtsZ is a homologue of eukaryotic tubulin and is essential in the process of cell division; it forms a contractile ring structure (Z ring) at the future cell division site. The regulation of the ring assembly controls the timing and the location of cell division. One of the functions of the FtsZ ring is to recruit other cell division proteins to the septum to produce a new cell wall between the dividing cells [, , ].Homologous from plants, such as AtFtsZ2-1, AtFtsZ1 and AtFtsZ2-2 are components of the plastid division machinery that forms a contractile ring at the division site and are required for plastid division in a dose-dependent manner []. Cetz, an archaeal tubulin-like protein related to tubulin and FtsZ, was initially annotated as FtsZ3 or FtsZ type 2, does not affect cell division, instead, it is involved in cell shape control, required for differentiation of the irregular plate-shaped cells into a rod-shaped cell type that is essential for normal swimming motility []. CetZ co-exists with FtsZ in many archaea. These proteins contain a GTPase domain that binds and hydrolyses GTP.
The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell []and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete effector proteins called YopB and YopD that facilitate the spread of other translocated proteins through the type III needle and the host cell cytoplasm []. In turn, the transcription of these moieties is thought to be regulated by another gene, lcrV, found on the Yops virulon that encodes the entire type III system []. The product of this gene, LcrV protein, also regulates the secretion of YopD through the type III translocon [], and itself acts as a protective "V"antigen for Yersinia pestis, the causative agent of plague [].Recently, a homologue of the Y. pestis LcrV protein (PcrV) was found in Pseudomonas aeruginosa, an opportunistic pathogen. In vivo studies using mice found that immunisation with the protein protected burned animals from infection by P. aeruginosa, and enhanced survival. In addition, it is speculated that PcrV determines the size of the needle pore for type III secreted effectors [].The structure of the virulence-associated V antigen consists of an all-alpha and alpha+beta domains connected by antiparallel coiled coil.
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [, ]. An empirical classification into three classes has been proposed by Fowler and coworkers []and Kojima []. Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units [].This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms []. The members of family 1 are recognised by the sequence pattern K-x(1,2)-C-C-x-C-C-P-x(2)-C located at the beginning of the third exon. The taxonomic range of the members extends to vertebrates. Known characteristics: 60 to 68 AAs; 20 Cys (21 in one case), 19 of them are totally conserved; the protein sequence is divided into two structural domains, containing 9 and 11 Cys all binding 3 and 4 bivalent metal ions, respectively.
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, nickel, etc. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [, ]. An empirical classification into three classes has been proposed by Fowler and coworkers []and Kojima []. Members of class I are defined to include polypeptides related in the positions of their cysteines to equine MT-1B, and include mammalian MTs as well as from crustaceans and molluscs. Class II groups MTs from a variety of species, including sea urchins,fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units [].This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Subsequently, a new classification was proposed on the basis of sequence similarity derived from phylogenetic relationships, which basically proposes an MT family for each main taxonomic group of organisms []. This entry includes metallothioneins from vertebrates []and MT-10 type metallothioneins from aquatic molluscs [].
Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase, ) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ [, , , ].This family also includes S-adenosylhomocysteine hydrolase-like 1 (Ahcyl1), also known as IRBIT, and S-adenosylhomocysteine hydrolase-like protein 2 (Ahcyl2). Ahcyl1/IRBIT was shown to interact with inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as intracellular Ca(2+) channels, and suppresses IP3 binding of IP3R [, ]. By competing with IP3, it modulates the threshold IP3 concentration required for the activation of the receptor []. Further studies indicate that Ahcyl1/IRBIT is in fact a multifunctional protein that regulates several ion channels and ion transporters [, ]. Despite its homology to S-adenosylhomocysteine hydrolases, Ahcyl1 has neither enzyme activity nor any effects on the enzyme activity of S-adenosylhomocysteine hydrolase []. Ahcyl2 lacks binding activity to IP3R []. Ahcyl2 upregulates NBCe1-B, which plays an important role in intracellular pH regulation [].
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 [].
Chloroperoxidase (CPO), also known as Heme haloperoxidase, is a ~250 residue heme-containing glycoprotein that is secreted by various fungi. Chloroperoxidase was first identified in Caldariomyces fumago where it catalyses the hydrogen peroxide-dependent chlorination of cyclopentanedione during the biosynthesis of the antibiotic caldarioymcin. Additionally, Heme haloperoxidase catalyses the iodination and bromination of a wide range of substrates. Besides performing H2O2-dependent halogenation reactions, the enzyme catalyses dehydrogenation reactions. Chloroperoxidase also functions as a catalase, facilitating the decomposition of hydrogen peroxide to oxygen and water. Furthermore, chloroperoxidase catalyses P450-like oxygen insertion reactions. The capability of chloroperoxidase to perform these diverse reactions makes it one of the most versatile of all known heme proteins [, ].Despite functional similarities with other heme enzymes, chloroperoxidase folds into a novel tertiary structure dominated by eight helical segments []. Structurally, chloroperoxidase is unique, but it shares features with both peroxidases and P450 enzymes. As in cytochrome P450 enzymes, the proximal heme ligand is a cysteine, but similar to peroxidases, the distal side of the heme is polar. However, unlike other peroxidases, the normally conserved distal arginine is lacking and the catalytic acid base is a glutamic acid and not a histidine [].
Members of this group are predicted signal transduction proteins containing cytoplasmic sensor domain GAF and an RNA-binding anti-terminator ANTAR domain.In members of this group, regulation/signal receiving is predicted to be performed by the GAF domain. GAF is a ubiquitous signalling/sensory domain. It has been originally described as a non-catalytic cGMP-binding domain conserved in cyclic nucleotide phosphodiesterases []. Subsequently, this domain was recognised in cyanobacterial adenylate cyclases, histidine kinases and certain other proteins []. It has been predicted to regulate allosterically catalytic activities via binding ligands, such as nucleotides and small molecules [].ANTAR is a transcriptional anti-terminator domain [, , ]and is most often found fused to the CheY-like receiver domain to form response regulator anti-terminator (). Superficially, the coiled-coil and three-helix bundle that form this domain in AmiR []() appear radically different from the compact HTHDNA-binding domain of the NarL protein. However, the last three helices in AmiR are very similar in length and hydropathy profiles to those of NarL and its homologues, and are arranged in a very similar topology, suggesting an evolutionary relationship []. These C-terminal helices of AmiR appear to be essential for its transcription anti-termination activity []. However, helix-turn-helix domains like those in NarL or OmpR []are adapted to sequence-specific binding in the major groove of double-stranded B-form DNA. It is not clear how such a structure might function in a protein whose role is to prevent the formation of a termination stem-loop structure, by binding single-stranded RNA [].
This entry represents the serine/threonine-protein kinase TOR (target of rapamycin), which was first identified by mutations in yeast that confer resistance to the growth inhibitory properties of rapamycin []. TOR proteins are structurally and functionally conserved in all eukaryotes examined. However, yeasts contain two Tor proteins (Tor1 and Tor2), while higher eukaryotes such as humans possess a single TOR protein []. They are central regulators of cellular metabolism, growth and survival in response environmental signals [, , ]. In budding yeast, the Tor2 protein exists in two distinct multi-component complexes, TORC1 and TORC2. TORC1 regulates cell growth by regulating many growth-related processes and is rapamycin sensitive, while TROC2 regulates the cell cytoskeleton and is rapamycin insensitive. Budding yeast TORC1 consists of either Tor1 or Tor2 in complex with Kog1, Lst8 and Tco89, while TORC2 is composed of Avo1, Avo2, Tsc11, Lst8, Bit61, Slm, Slm2 and Tor2 [, ]. In both yeast and mammals, FKBP12-rapamycin binds to Tor (Tor1, Tor2, or mTOR) in TORC1, but not to Tor (Tor2 or mTOR) in TORC2. It has been suggested that the architecture of TORC2 or its unique composition might be responsible for the observed rapamycin resistance [].
Fructose-1,6-bisphophatase (FBPase) catalyses the hydrolysis of D-fructose-1,6-bisphosphate (FBP) to D-fructose-6-phopshate (F6P) and orthophosphate, and is a key enzyme in gluconeogenesis []. Three different groups of FBPases have been identified in eukaryotes and bacteria (FBPase I-III) []. None of these groups have been found in archaea so far, though a new group of FBPases (FBPase IV) which also show inositol monophosphatase activity has recently been identified in archaea [].Proteins in this entry are though to represent a new group of FBPases (FBPase V) which are found in thermophilic archaea and a hyperthermophilic bacterium Aquifex aeolicus []. The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organisms [, ]. A structural study suggests that FBPase V has a novel fold for a sugar phosphatase, forming a four-layer α-β-beta-alpha sandwich, unlike the more usual five-layered α-β-α-β-alpha arrangement []. The arrangement of the catalytic side chains and metal ligands was found to be consistent with the three-metal ion assisted catalysis mechanism proposed for other FBPases.
Diol dehydratase () and glycerol dehydratase () are two iso-functional enzymes that can each catalyse the conversion of 1,2-propanediol, 1,2-ethanediol and glycerol to the corresponding deoxy aldehydes(propionaldehyde, acetaldehyde and 3-hydroxypropionaldehyde, respectively). This reaction proceeds by a radical mechanism involving coenzyme B12 (adenosylcobalamin, AdoCbl) as an essential cofactor. Even though they catalyse the same reaction, these two enzymes (1) differ in their substrate preferences (diol dehydratase has a higher affinity for 1,2-propanediol and glycerol dehydratase for glycerol []); (2) they participate in different pathways (dihydroxyacetone [DHA]pathway for glycerol dehydratase and 1,2-propanediol degradation pathway for diol dehydratase); and (3) in those organisms where both enzymes are produced (such as Klebsiella and Citrobacter), the genes for them are independently regulated: glycerol dehydratase is induced when Klebsiella pneumoniae grows in glycerol-containing medium, whereas diol dehydratase is fully induced when it grows in propane-1,2-diol-containing medium, but only slightly in the glycerol medium [, ]. Crystal structures, mechanism of action and structure-function relationship with the coenzyme B12 have been extensively studied for these enzymes []. Diol/glycerol dehydratases undergo inactivation during catalysis and require a reactivating factor. Propanediol dehydratase was found to be associated with and is believed to be encased in the proteinaceous shell of polyhedral organelles [].Both diol dehydratase and glycerol dehydratase comprise three subunits: PduC/PduD/PduE or PddA/PddB/PddC for propanediol dehydratase, and GldA/Gld/B/GldC or DhaB/DhaC/DhaE for glycerol dehydratase. This entry represents the small subunit PduE/PddC/GldC/DhaE. The structure of dehydratase consists of three helices.
Signal transduction by T and B cell antigen receptors and certain receptorsfor Ig Fc regions involves a conserved sequence motif, termed animmunoreceptor tyrosine-based activation motif (ITAM). It is also found in thecytoplasmic domain of the apoptosis receptor. Phosphorylation of the two ITAMtyrosines is a critical event in signal transduction. All (p)2ITAMs, but nottheir nonphosphorylated counterparts, induced extensive protein tyrosinephosphorylation in permeabilised cells. After binding of the ligand via an SH2domain, phosphorylation of the two conserved tyrosines of ITAM creates binding sites for downstream signalling molecules and thus enables the initiation of signalling events. This phosphorylation was found to reflect activation of the src family kinases Lyn and Syk. Different ITAMs may preferentially activate distinct signalling pathways as a consequence of distinct SH2 effector binding preference [, ]. Furthermore, in viruses, ITAMs may play key roles in viral pathogenesis by regulating viral clearance, immune cell activation, immune cell recruitment through binding of cellular kinases and thereby down regulate their function [].This motif can be found in one to three copies and in association with the Ig-like domain. Proteins currently known to contain an ITAM motif are:Mammalian alpha and beta immunoglobulin proteins, TCR gamma receptors, FCR gamma receptors subunits, CD3 chains receptors and NFAT activation molecule.Hantavirus cytoplasmic elements.
Synonym: dark protochlorophyllide reductaseProtochlorophyllide reductase catalyzes the reductive formation of chlorophyllide from protochlorophyllide during biosynthesis of chlorophylls and bacteriochlorophylls. Three genes, bchL, bchN and bchB, are involved in light-independent protochlorophyllide reduction in bacteriochlorophyll biosynthesis. In cyanobacteria, algae, and gymnosperms, three similar genes, chlL, chlN and chlB are involved in protochlorophyllide reduction during chlorophylls biosynthesis. BchL/chlL, bchN/chlN and bchB/chlB exhibit significant sequence similarity to the nifH, nifD and nifK subunits of nitrogenase, respectively. Nitrogenase catalyzes the reductive formation of ammonia from dinitrogen []. The light-independent (dark) form of protochlorophyllide reductase plays a key role in the ability of gymnosperms, algae, and photosynthetic bacteria to form chlorophyll in the dark. Genetic and sequence analyses have indicated that dark protochlorophyllide reductase consists of three protein subunits that exhibit significant sequence similarity to the three subunits of nitrogenase, which catalyzes the reductive formation of ammonia from dinitrogen. Dark protochlorophyllide reductase activity was shown to be dependent on the presence of all three subunits, ATP, and the reductant dithionite.The BchL peptide (ChlL in chloroplast and cyanobacteria) is an ATP-binding iron-sulphur protein of the dark form protochlorophyllide reductase, an enzyme similar to nitrogenase [].
Fructose-1,6-bisphophatase (FBPase) catalyses the hydrolysis of D-fructose-1,6-bisphosphate (FBP) to D-fructose-6-phopshate (F6P) and orthophosphate, and is a key enzyme in gluconeogenesis []. Three different groups of FBPases have been identified in eukaryotes and bacteria (FBPase I-III) []. None of these groups have been found in archaea so far, though a new group of FBPases (FBPase IV) which also show inositol monophosphatase activity has recently been identified in archaea [].Proteins in this entry are though to represent a new group of FBPases (FBPase V) which are found in thermophilic archaea and a hyperthermophilic bacterium Aquifex aeolicus []. The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organisms [, ]. A structural study suggests that FBPase V has a novel fold for a sugar phosphatase, forming a four-layer α-β-beta-alpha sandwich, unlike the more usual five-layered α-β-α-β-alpha arrangement []. The arrangement of the catalytic side chains and metal ligands was found to be consistent with the three-metal ion assisted catalysis mechanism proposed for other FBPases.
This entry represents a peptidase Vpr-like domain, found in a subgroup of proteins that belong to the peptidase family S8, subfamily S8A (subtilisin) []. The maturation of the peptide antibiotic (lantibiotic) subtilin in Bacillus subtilisATCC 6633 includes post-translational modifications of the propeptide and proteolytic cleavage of the leader peptide. Vpr (MEROPS identifier S08.114) was identified as one of the endopeptidases, along with WprA and AprE, that are capable of processing subtilin []. Vpr is secreted and synthesized as an auto-processing precursor, and has been shown to be fibrinolytic []. This entry also includes the FT peptidase from Bacillussp. KSM-KP43 (S08.117) [].The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence []. It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses []. The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase [, ]. Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity [, ]. Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein [].
Herpesviruses are dsDNA viruses with no RNA stage. This entry represents a conserved domain found in several Herpes viruses glycoproteins, including:Glycoprotein-D (gD or gIV), which is common to Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2), as well as Equid herpesvirus 1, Bovine herpesvirus 1 and Meleagrid herpesvirus 1 (MeHV-1). Glycoprotein-D has been found on the viral envelope and the plasma membrane of infected cells. gD immunisation can produce an immune response to bovine herpes virus (BHV-1). This response is stronger than that of the other major glycoproteins gB (gI) and gC (gIII) in BHV-1 [, , , ].Glycoprotein G (gG), which is one of the seven external glycoproteins of Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2) []. In the HHV-2 virus-infected cell, gG-2 iscleaved into a secreted amino-terminal portion (sgG-2) and a carboxy-terminal portion. The latter protein is further O-glycosylated, generating the cell membrane-associated mature gG-2 (mgG-2). The mgG-2 protein has widely been used as a prototype antigen for detection of type-specific antibodies against HHV-2 [].Glycoprotein GX (gX), which was initially identified in Suid herpesvirus 1 (Pseudorabies virus).
Members of this entry are similar to gene products 9 (gp9) and 10 (gp10) of bacteriophage T4. Both proteins are components of the viral baseplate []. Gp9 connects the long tail fibres of the virus to the baseplate and triggers tail contraction after viral attachment to a host cell. The protein is active as a trimer, with each monomer being composed of three domains. The N-terminal domain consists of an extended polypeptide chain and two alpha helices. The alpha1 helix from each of the three monomers in the trimer interacts with its counterparts to form a coiled-coil structure. The middle domain is a seven-stranded β-sandwich that is thought to be a novel protein fold. The C-terminal domain is thought to be essential for gp9 trimerisation and is organised into an eight- stranded antiparallel β-barrel, which was found to resemble the 'jelly roll' fold found in many viral capsid proteins. The long flexible region between the N-terminal and middle domains may be required for the function of gp9 to transmit signals from the long tail fibres []. Together with gp11, gp10 initiates the assembly of wedges that then go on to associate with a hub to form the viral baseplate [].
Many bacterial transcription regulation proteins bind DNA through a helix-turn-helix (HTH) motif, which can be classified into subfamilies on the basis of sequence similarities. The HTH GntR family has many members distributed among diverse bacterial groups that regulate various biological processes. It was named GntR after the Bacillus subtilis repressor of the gluconate operon []. Family members include GntR, HutC, KorA, NtaR, FadR, ExuR, FarR, DgoR and PhnF. The crystal structure of the FadR protein has been determined []. In general, these proteins contain a DNA-binding HTH domain at the N terminus, and an effector-binding or oligomerisation domain at the C terminus (). The DNA-binding domain is well conserved in structure for the whole of the GntR family, consisting of a 3-helical bundle core with a small β-sheet (wing); the GntR winged helix structure is similar to that found in several other transcriptional regulator families. The regions outside the DNA-binding domain are more variable and are consequently used to define GntR subfamilies []. This entry represents the N-terminal DNA-binding domain of the GntR family.
This entry represents the RNA recognition motif 2 (RRM2) of Musashi-1, which is a highly conserved RNA binding protein that was initially identified in Drosophila by its ability to regulate sensory organ development and asymmetric cell division []. Mammalian Musashi-1 has multiple functions in normal and abnormal processes by mediating different post-transcriptional processes. It has been implicated in the maintenance of the stem-cell state, differentiation, and tumorigenesis. It translationally regulates the expression of a mammalian numb gene by binding to the 3'-untranslated region of mRNA of Numb, encoding a membrane-associated inhibitor of Notch signaling, and further influences neural development []. Moreover, Musashi-1 represses translation by interacting with the poly(A)-binding protein and competes for binding of the eukaryotic initiation factor-4G (eIF-4G) [].Proteins containing this domain also includes Musashi-2, which has been identified as a regulator of the hematopoietic stem cell (HSC) compartment and of leukemic stem cells after transplantation of cells with loss and gain of function of the gene []. It influences proliferation and differentiation of HSCs and myeloid progenitors, and further modulates normal hematopoiesis and promotes aggressive myeloid leukemia [, ]. Musashi-1 and Musashi-2 contain two conserved N-terminal tandem RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), along with other domains of unknown function
This entry represents the RNA recognition motif 1 (RRM1) of Musashi-1, which is a highly conserved RNA binding protein that was initially identified in Drosophila by its ability toregulate sensory organ development and asymmetric cell division []. Mammalian Musashi-1 has multiple functions in normal and abnormal processes by mediating different post-transcriptional processes. It has been implicated in the maintenance of the stem-cell state, differentiation, and tumorigenesis. It translationally regulates the expression of a mammalian numb gene by binding to the 3'-untranslated region of mRNA of Numb, encoding a membrane-associated inhibitor of Notch signaling, and further influences neural development []. Moreover, Musashi-1 represses translation by interacting with the poly(A)-binding protein and competes for binding of the eukaryotic initiation factor-4G (eIF-4G) [].Proteins containing this domain also includes Musashi-2, which has been identified as a regulator of the hematopoietic stem cell (HSC) compartment and of leukemic stem cells after transplantation of cells with loss and gain of function of the gene []. It influences proliferation and differentiation of HSCs and myeloid progenitors, and further modulates normal hematopoiesis and promotes aggressive myeloid leukemia [, ]. Musashi-1 and Musashi-2 contain two conserved N-terminal tandem RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), along with other domains of unknown function.
Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium and nickel. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds [, , ]. An empirical classification into three classes was proposed by Kojima [], with class III MTs including atypical polypeptides composed of gamma-glutamylcysteinyl units. Class I and class II MTs (the proteinaceous sequences) have now been grouped into families of phylogenetically-related and thus alignable sequences. The MT superfamily is subdivided into families, subfamilies, subgroups, and isolated isoforms and alleles. The metallothionein superfamily comprises all polypeptides that resemble equine renal metallothionein in several respects [], e.g., low molecular weight; high metal content; amino acid composition with high Cys and low aromatic residue content; unique sequence with characteristic distribution of cysteines, and spectroscopic manifestations indicative of metal thiolate clusters. A MT family subsumes MTs that share particular sequence-specific features and are thought to be evolutionarily related. Fifteen MT families have been characterised, each family being identified by its number and its taxonomic range.Family 14 consists of prokaryota MTs. Its members are recognised by the sequence pattern K-C-A-C-x(2)-C-L-C.The taxonomic range of the members extends to cyanobacteria. Known characteristics are: 53 to 56 AAs; 9 conserved Cys; one conserved tyrosine residue; one conserved histidine residue; contain other unusual residues.
RNA cyclases are a family of RNA-modifying enzymes that are conserved in eukaryotes, bacteria and archaea. RNA 3'-terminal phosphate cyclase () [, ]catalyses the conversion of 3'-phosphate to a 2',3'-cyclic phosphodiester at the end of RNA.ATP + RNA 3'-terminal-phosphate = AMP + diphosphate + RNA terminal-2',3'-cyclic-phosphateThese enzymes might be responsible for production of the cyclic phosphate RNA ends that are known to be required by many RNA ligases in both prokaryotes and eukaryotes.RNA cyclase is a protein of from 36 to 42kDa. The best conserved region is aglycine-rich stretch of residues located in the central part of the sequence and which is reminiscent of various ATP, GTP or AMP glycine-rich loops.The crystal structure of RNA 3'-terminal phosphate cyclase shows that each molecule consists of two domains. The larger domain contains three repeats of a folding unit comprising two parallel alpha helices and a four-stranded beta sheet; this fold was previously identified in translation initiation factor 3 (IF3). The large domain is similar to one of the two domains of 5-enolpyruvylshikimate-3-phosphate synthase and UDP-N-acetylglucosamine enolpyruvyl transferase. The smaller insert domain disrupts the large domain, and uses a similar secondary structure element with different topology, observed in many other proteins such as thioredoxin []. Although the active site of this enzyme could not be unambiguously assigned, it can be mapped to a region surrounding His309, an adenylate acceptor, in which a number of amino acids are highly conserved in the enzyme from different sources []. This superfamily represents the small insert domain that interrupts the large repetitive domain.
This entry represents the SOS response associated peptidase (SRAP) superfamily.The SRAP (SOS-response associated peptidase) family is characterised by the SRAP domain with a novel thiol autopeptidase activity, whose active site in human HMCES is comprised of the catalytic triad residues C2, E127, and H210 []. SRAP proteins are evolutionarily conserved in all domains of life. For instance, human HMCES and E. coli YedK are similar in both sequence and structure []. HMCES was originally identified as a possible reader of 5hmC in embryonic stem cell extracts using a double-stranded DNA molecule containing 5hmC as bait []. The bacterial members have operonic associations with the SOS DNA damage response, mutagenic translesion DNA polymerases, non-homologous DNA-ending-joining networks that employ Ku and an ATP-dependent ligase, and other repair systems []. Abasic (AP) sites are one of the most common DNA lesions that block replicative polymerases. SRAP proteins shield the AP site from endonucleases and error-prone polymerases []. Both HMCES and YedK have been found to preferentially bind ssDNA and efficiently form DNA-protein crosslinks (DPCs) to AP sites in ssDNA. They crosslink to AP sites via a stable thiazolidine DNA-protein linkage formed with the N-erminal cysteine and the aldehyde form of the AP deoxyribose []. In B Cells, HMCES has also been shown to mediate microhomology-mediated alternative-end-joining through its SRAP domain [].
X-linked lissencephaly is a severe brain malformation affecting males. Recently it has been demonstrated that the doublecortin gene is implicated in this disorder []. Doublecortin was found to bind to the microtubule cytoskeleton. In vivo and in vitro assays show that Doublecortin stabilises microtubules and causes bundling []. Doublecortin is a basic protein with an iso-electric point of 10, typical of microtubule-binding proteins. However, its sequence contains no known microtubule-binding domain(s).The detailed sequence analysis of Doublecortin and Doublecortin-like proteins allowed the identification of an evolutionarily conserved Doublecortin (DC) domain, which is ubiquitin-like. This domain is found in the N terminus of proteins and consists of one or two tandemly repeated copies of an around 80 amino acids region. It has been suggested that the first DC domain of Doublecortin binds tubulin and enhances microtubule polymerisation [].Some proteins known to contain a DC domain are listed below:Doublecortin. It is required for neuronal migration []. A large number of point mutations in the human DCX gene leading to lissencephaly are located within the DC domains [].Human serine/threonine-protein kinase DCAMKL1. It is a probable kinase that may be involved in a calcium-signaling pathway controlling neuronal migration in the developing brain [, ].Retinitis pigmentosa 1 protein. It is required for the differentiation of photoreceptor cells. Mutation in the human RP1 gene cause retinitis pigmentosa of type 1 [, ].
The anti-apoptotic protein p35 from baculovirus is thought to prevent the suicidal response ofinfected insect cells by inhibiting caspases. Ectopic expression of p35 in a number of transgenic animals or cell lines is also anti-apoptotic, giving rise to the hypothesis that the protein is a general inhibitor of caspases. This protein belongs to MEROPS proteinase inhibitor family I50, clan IQ. Purified recombinant p35 inhibits human caspase-1, -3, -6, -7, -8, and -10 but does not significantly inhibit unrelated serine or cysteine proteases, implying that p35 is a potent caspase-specific inhibitor. The interaction of p35 with caspase-3, as a model of the inhibitory mechanism,revealed classic slow-binding inhibition, with both active-sites of the caspase-3 dimer acting equally and independently. Inhibition resulted from complex formation between the enzyme and inhibitor, which could be visualised under non-denaturing conditions, but was dissociated by SDS to give p35 cleaved at Asp87, the P1 residue of the inhibitor. Complex formation requires the substrate-binding cleft to be unoccupied [].Infecting the insect cell line IPLB-Ld652Y with the baculovirus Autographa californica nuclear polyhedrosis virus (AcMNPV) results in global translation arrest, which correlates with the presence of the AcMNPV apoptotic suppressor, p35. However, the anti-apoptotic function of p35 in translation arrest is not solely due to caspase inactivation, but its activity enhances signalling to a separate translation arrest pathway, possibly by stimulating the late stages of the baculovirus infection cycle []. The baculovirus p35 structure forms a sandwich composed of 14 strands in 2 sheets with a greek-key topology.
Chorismate synthase (CS; 5-enolpyruvylshikimate-3-phosphate phospholyase; 1-carboxyvinyl-3-phosphoshikimate phosphate-lyase; E.C. 4.2.3.5) catalyzes the seventh and final step in the shikimate pathway which is used in prokaryotes, fungi and plants for the biosynthesis of aromatic amino acids. It catalyzes the 1,4-trans elimination of the phosphate group from 5-enolpyruvylshikimate-3-phosphate (EPSP) to form chorismate which can then be used in phenylalanine, tyrosine or tryptophan biosynthesis. Chorismate synthase requires the presence of a reduced flavin mononucleotide (FMNH2 or FADH2) for its activity. Chorismate synthase from various sources shows a high degree of sequence conservation [, ]. It is a protein of about 360 to 400 amino-acid residues.Depending on the capacity of these enzymes to regenerate the reduced form of FMN, chorismate synthases are divided into two groups: enzymes, mostly from plants and eubacteria, that sequester CS from the cellular environment, are monofunctional, while those that can generate reduced FMN at the expense of NADPH, such as found in fungi and the ciliated protozoan Euglena gracilis, are bifunctional, having an additional NADPH:FMN oxidoreductase activity. Recently, bifunctionality of the Mycobacterium tuberculosis enzyme (MtCS) was determined by measurements of both chorismate synthase and NADH:FMN oxidoreductase activities. Since shikimate pathway enzymes are present in bacteria, fungi and apicomplexan parasites (such as Toxoplasma gondii, Plasmodium falciparum, and Cryptosporidium parvum) but absent in mammals, they are potentially attractive targets for the development of new therapy against infectious diseases such as tuberculosis (TB) [, , , , , , , , , ].
The transcription factor NF-kB (Nuclear Factor-kappaB) was first identified as a DNA-binding protein specific for the 10-base pair kB site in the immunoglobulin k light-chain enhancer of B lymphocytes [], but has subsequently been found in many different cell types. NF-kB represents a group of structurally related proteins that share a 300 amino acid `Rel homology domain' (RHD) []: members include p50 (NF-kB1), p52 (NF-kB2), p65 (RelA), c-Rel, v-Rrel, RelB, and the Drosophila proteins Dorsal and Dif. These proteins exist as homo- and heterodimers that bind to kB sites in the enhancer regions of several target genes, most of which are involved in cellular defence mechanisms and differentiation.The RHD, which is located N-terminally, is responsible for proteindimerisation, DNA binding and nuclear localisation. The more variableC-terminal transactivation domain is found in RelA, RelB and c-Rel, but not in p50 or p52. Nevertheless, p50 and p52 play critical roles in modulatingthe specificity of NF-kB function. DNA binding requires the entire RHD, by contrast with other eukaryotic and prokaryotic transcription factors, where muchsmaller DNA-binding domains confer full specificity and bindingaffinity for the target []. The structure of the transcription factor NF-kB p50 homodimer bound to a palindromic kB site shows the RHD to fold into 2 distinct subdomains, similar to the β-sandwich structure of the immunoglobulins [].NF-kB is expressed in the cytoplasm of virtually all cell types, where its activity is controlled by a family of regulatory proteins, called inhibitors of NF-kB (IkB) [, ].
The jacalin-like mannose-binding lectin domain has a β-prism fold consisting of three 4-stranded β-sheets, with an internal pseudo 3-fold symmetry. Some proteins with this domain stimulate distinct T- and B- cell functions, such as the plant lectin jacalin, which binds to the T-antigen and acts as an agglutinin. The domain can occur in tandem-repeat arrangements with up to six copies, and in architectures combined with a variety of other functional domains. While the family was initially named after an abundant protein found in the jackfruit seed, taxonomic distribution is not restricted to plants. The domain is also found in the salt-stress induced protein from rice and an animal prostatic spermine-binding protein. Proteins containing this domain include:Jacalin, a tetrameric plant seed lectin and agglutinin from Artocarpus heterophyllus (jackfruit), which is specific for galactose [].Artocarpin, a tetrameric plant seed lectin from A. heterophyllus [].Lectin MPA, a tetrameric plant seed lectin and agglutinin from Maclura pomifera (Osage orange), [].Heltuba lectin, a plant seed lectin and agglutinin from Helianthus tuberosus (Jerusalem artichoke) [].Agglutinin from Calystegia sepium (Hedge bindweed) [].Griffithsin, an anti-viral lectin from red algae (Griffithsia species) [].
This entry represents the N-terminal domain of YopH protein tyrosine phosphatase (PTP). This domain has a compact structure composed of four α-helices and two β-hairpins. Helices alpha-1 and alpha-3 are parallel to each other and antiparallel to helices alpha-2 and alpha-4. This domain targets YopH for secretion from the bacterium and translocation into eukaryotic cells, and has phosphotyrosyl peptide-binding activity, allowing for recognition of p130Cas and paxillin []. YopH from Yersinia sp. is essential for pathogenesis, as it allows the bacteria to resist phagocytosis by host macrophages through its ability to dephosphorylate host proteins, thereby interfering with the host signalling process. Yersinia has one of the most active PTP enzymes known. YopH contains a loop of ten amino acids (the WPD loop) that covers the entrance of the active site of the enzyme during substrate binding []. A homologous domain is found in YscM (Yop secretion protein M or Yop proteins translocation protein M), which acts as a Yop protein translocation protein. Several Yop proteins are involved in pathogenesis. YscM is produced by the virulence operon virC, which encodes thirteen genes, yscA-M []. Transcription of the virC operon was subjected to the same regulation as the yop genes.
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT delta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT beta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT alpha subunit (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Proteins in this entry consist exclusively of the CCT gamma chain from animals, plants, fungi, and other eukaryotes.Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT epsilon chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Glycogen synthase kinase 3 (GSK3) is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress [, ]. In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress []. In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly [].Mammals have two isoforms of GSK3, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini []. They are both involved in axon formation and in Wnt signaling [, ]. They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry []. GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others [, , ].
This entry represents the regulator of ribonuclease E activity A (RraA). These proteins contain a swivelling 3-layer beta/beta/alpha domain that appears to be mobile in most multi-domain proteins known to contain it. These proteins are structurally similar, and may have distant homology, to the phosphohistidine domain of pyruvate phosphate dikinase. The RraA fold is an ancient platform that has been adapted for a wide range of functions. RraA had been identified as a putative demethylmenaquinone methyltransferase and was annotated as MenG, but further analysis showed that RraA lacked the structural motifs usually required for methylases []. The Escherichia coli protein regulator RraA acts as a trans-acting modulator of RNA turnover, binding essential endonuclease RNase E and inhibiting RNA processing []. RNase E forms the core of a large RNA-catalysis machine termed the degradosomes. RraA (and RraB) causes remodelling of degradosome composition, which is associated with alterations in RNA decay and global transcript abundance and as such is a bacterial mechanism for the regulation of RNA cleavage.This fold is also found in 4-hydroxy-4-methyl-2-oxoglutarate aldolase, also known as RraA-like protein []and at the C terminus of the DlpA protein .
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT zeta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT theta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
Members of this eukaryotic family are part of the group II chaperonin complex called CCT (chaperonin containing TCP-1 or Tailless Complex Polypeptide 1) or TRiC [, ]. Chaperonins are involved in productive folding of proteins []. They share a common general morphology, a double toroid of 2 stacked rings. The archaeal equivalent group II chaperonin is often called the thermosome []. Both the thermosome and the TCP-1 family of proteins are weakly, but significantly [], related to the cpn60/groEL chaperonin family (see ).The TCP-1 protein was first identified in mice where it is especially abundant in testis but present in all cell types. It has since been found and characterised in many other animal species, as well as in yeast, plants and protists. The TCP1 complex has a double-ring structure with central cavities where protein folding takes place []. TCP-1 is a highly conserved protein of about 60kDa (556 to 560 residues) which participates in a hetero-oligomeric 900kDa double-torus shaped particle []with 6 to 8 other different, but homologous, subunits []. These subunits, the chaperonin containing TCP-1 (CCT) subunit beta, gamma, delta, epsilon, zeta and eta are evolutionary related to TCP-1 itself [, ]. Non-native proteins are sequestered inside the central cavity and folding is promoted by using energy derived from ATP hydrolysis [, , ]. The CCT is known to act as a molecular chaperone for tubulin, actin and probably some other proteins [, ].This family consists exclusively of the CCT eta chain (part of a paralogous family) from animals, plants, fungi, and other eukaryotes.
The ERM family consists of three closely-related proteins, ezrin, radixin and moesin []. Ezrin was first identified as a constituent of microvilli [], radixin as a barbed, end-capping actin-modulating protein from isolated junctional fractions [], and moesin as a heparin binding protein [], which is particularly important in immunity acting on both T and B-cells homeostasis and self-tolerance [, ]. Members of this family have been associated with axon-associated Schwann cell (SC) motility and the maintenance of the polarity of these cells []. A tumour suppressor molecule responsible for neurofibromatosis type 2 (NF2) is highly similar to ERM proteins and has been designated merlin (moesin-ezrin-radixin-like protein) []. ERM molecules contain 3 domains, an N-terminal globular domain, an extended α-helical domain and a charged C-terminal domain []. Ezrin, radixin and merlin also contain a polyproline region between the helical and C-terminal domains. The N-terminal domain is highly conserved, and is also found in merlin, band 4.1 proteins and members of the band 4.1 superfamily, designated the FERM domain []. ERM proteins crosslink actin filaments with plasma membranes. They co-localise with CD44 at actin filament plasma membrane interaction sites, associating with CD44 via their N-terminal domains and with actin filaments via their C-terminal domains []. The α-helical region is involved in intramolecular masking of protein-protein interaction sites which regulates the activity of this proteins [].
