The Repressor Element-1 (RE-1) Silencing Transcription (REST) factor is a transcriptional repressor which binds neuron-restrictive silencer element (NRSE) and represses neuronal gene transcription in non-neuronal cells [, ]. REST is involved in neural differentiation and in preservation of the neural phenotype. REST also plays a role in proliferation, although its effect differs depending on the cell type [].
YjbE is part of a four gene operon which is involved in exopolysaccharide production. The expression of YjbE is higher than the rest of the operon yjbEFGH. It appears to be restricted to Enterobacteriaceae [].
Recently, the generic name 'NUDIX hydrolases' (NUcleoside DIphosphate linke to some other moeity X) has been coined for this domain family []. The family can be divided into a number of subgroups, of which MutT anti-mutagenic activity represents only one type; most of the rest hydrolyse diverse nucleoside diphosphate derivatives (including ADP-ribose, GDP-mannose, TDP-glucose, NADH, UDP-sugars, dNTP and NTP).
This EGF-like domain is found at the C terminus of the malaria parasite MSP1 protein. MSP1 is the merozoite surface protein 1. This domain is part of the C-terminal fragment that is proteolytically processed from the the rest of the protein and is left attached to the surface of the invading parasite [].
This entry represents a short N-terminal domain at the start of small glutamine-rich tetratricopeptide repeat-containing protein (SGTA), a heat-shock protein (HSP) co-chaperone involvedin the targeting of tail-anchor membrane proteins to the endoplasmic reticulum. This is the homodimerisation domain that mediates the association with a single copy of Get4 or Get5 proteins, providing a link to the rest of the GET pathway [].
Brain and reproductive organ-expressed (BRE, also known as BRCC45) is a component of the BRCA1-A complex, a complex that specifically recognises 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs) []. It acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer [, ]. It is also part of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates [, , , ]. Within the BRISC complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity [].
The MTC family consists of a limited number of homologues, all from eukaryotes. One member of the family has been functionally characterised as a tricarboxylate carrier from rat liver mitochondria. The rat liver mitochondrial tricarboxylate carrier has been reported to transport citrate, cis-aconitate, threo-D-isocitrate, D- and L-tartrate, malate, succinate and phosphoenolpyruvate. It presumably functions by a proton symport mechanism. The rest of the characterised proteins appear to be sideroflexins involved in iron transport.
The subunit composition of glycine cleavage system P-proteins have been classified into two types. Those from eukaryotes and some of the P-proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukariotic-subunit [].This entry represents the probable glycine dehydrogenase (decarboxylating) subunit 1 from prokaryotes.
This domain lies at the C terminus of the DNA polymerase III subunit delta. Within the clamp loader gamma complex of the DNA polymerase III, several C-terminal domains, of gamma, delta and delta' form a helical scaffold, on which the rest of he subunits are hung. The gamma complex, an AAA+ ATPase, is the bacterial homologue of the eukaryotic replication factor C that loads the sliding clamp (beta, homologous to PCNA) onto DNA [].
The bluetongue virus (BTV) is a representative of the orbivirus genus of the Reoviridae. The crystal structure of VP7 from BTV serotype 10 reveals that the central one third of the polypeptide chain (residues 121-249) is folded into a β-sandwich. The rest of the polypeptide (residues 1-120 and 250-349) is composed of nine α-helices and long extended loops [].This superfamily represents the N-terminal domain, consisting of five α-helices.
The bluetongue virus (BTV) is a representative of the orbivirus genus of the Reoviridae. The crystal structure of VP7 from BTV serotype 10 reveals that the central one third of the polypeptide chain (residues 121-249) is folded into a β-sandwich. The rest of the polypeptide (residues 1-120 and 250-349) is composed of nine α-helices and long extended loops [].This superfamily represents the C-terminal domain consisting of four α-helices.
Pho85 is a non-essential cyclin-dependent kinase (CDK) involved in the cell cycle []. Pho85 is controlled by 10 cyclins that may be grouped into 2 families according to cyclin box sequence similarity []: the Pho80 family (Pho80, Pcl6, Pcl7, Pcl8, and Pcl10) and the Pcl1,2 family (Pcl1, Pcl2, Pcl5, Pcl9 and ClG1). Except Pcl5, the rest of the Plc1,2 family members show a tightly controlled cell cycle pattern of expression: Pcl9 is produced in late M phase and during early G1, Pcl2 in late M until late G1, and Pcl1 during late G1 [].This entry includes Pcl1, Pcl2 and Pcl9.
Thisfamily consists of known phosphorylases, and homologues believed to share the function of using inorganic phosphate to cleave an alpha 1,4 linkage between the terminal glucose residue and the rest of the polymer (maltodextrin, glycogen, etc.). The name of the glucose storage polymer substrate, and therefore the name of this enzyme, depends on the chain lengths and branching patterns. A number of the members of this family have been shown to operate on small maltodextrins, as may be obtained by utilization of exogenous sources. This family represents a distinct clade from the related families: Glycogen/starch/alpha-glucan phosphorylase and Glycosyl transferase, family 35.
PRKCBP1 is a novel receptor for activated C-kinase (RACK)-like protein that may play an important role in the activation and regulation of PKC-beta I, and the PKC signaling cascade []. It also has been identified as a formin homology-2-domain containing protein 1 (FHOD1)-binding protein that may be involved in FHOD1-regulated actin polymerisation and transcription []. Moreover, PRKCBP1 may function as a REST co-repressor 2 (RCOR2) interacting factor; the RCOR2/ZMYND8 complex which might be involved in the regulation of neural differentiation []. PRKCBP1 contains a plant homeodomain (PHD) finger, a bromodomain, and a proline-tryptophan-tryptophan-proline (PWWP) domain.This entry represents the PHD finger domain.
The replicase polyproteins of the Nidoviruses such as, porcine arterivirus PRRSV, equine arterivirus EAV, human coronavirus 229E, and severe acute respiratory syndrome coronavirus (SARS-CoV), are predicted to be cleaved into 14 non-structural proteins (nsps) by the nsp4 main proteinase and three accessory proteinases residing in nsp1-alpha, nsp1-beta and nsp2 [, , ].This entry represents the two nsp1 proteins that together act in a papain-like way to separate off the rest of the various functional domains of the polyprotein. Once inside the host cell, this nsp1 interferes with the regulation of interferon, thereby enabling the virus to replicate [, ].
Sin3a is a transcriptional repressor and a homologue of the SIN3 repressor from yeast. Sin3a associates with the strong repressive isoform of Mxi1, a helix-loop-helix leucone zipper that associates with Max to antagonize Myc oncogenic activities []. Unlike Mxi1 and Myc, expression of Sin3a does not vary during development []. Sin3a is a component of several complexes, including the REST-CoREST repressor complex [], the PER complex which maintains circadian rhythm []and the Sin3 HDAC complex []. Sin3a also interacts with FOXK1 to regulate cell cycle progression []. Sin3a has three PAH domains by which it interacts with HCFC1, REST and SAP30 [, ].
Tex (toxin expression) is a highly conserved bacterial protein involved in expression of critical toxin genes []. The overall structure is notably flat and elongated. The most striking structural feature is a long, central helix comprising from amino acid residue 274 to 322. The rest of the protein wraps around the central helix at both the N-terminal and C-terminal ends. Although the Tex structure is fairly compact, it can be largely described as a series of distinct domains [].This superfamily represents a domain comprising amino acids 115-327 and 456-502, flanking the YqgF domain ().
The Cnd1-3 proteins are the three non-SMC (structural maintenance of chromosomes) proteins that go to make up the mitotic condensation complex along with the two SMC protein families, XCAP-C and XCAP-E, (or in the case of fission yeast, Cut3 and Cut14) []. The five-member complex seems to be conserved from yeasts to vertebrates. This domain is the C-terminal, cysteine-rich domain of Cnd3. The complex shuttles between the nucleus, during mitosis, and the cytoplasm during the rest of the cycle. Thus this family is made up of the C-termini of XCAP-Gs, Ycg1 and Ycs5 members.
Tex (toxin expression) is a highly conserved bacterial protein involved in expression of critical toxin genes []. The overall structure is notably flat and elongated. The most striking structural feature is a long, central helix comprising from amino acid residue 274 to 322. The rest of the protein wraps around the central helix at both the N-terminal and C-terminal ends. Although the Tex structure is fairly compact, it can be largely described as a series of distinct domains [].This superfamily represents an N-terminal domain with a helix-turn-helix structure.
This entry represent the N-terminal transit peptide of a number of algal petF genes. The peptide is removed during transit into the chloroplast lumen. The structure of chloroplast ferredoxin in water is unstructured however in a 30:70 molar-ratio mixture of 2,2,2-trifluoroethanol, residues 3 to 13 form an α-helix. The rest of the peptide remains unstructured []. This domain is the N-terminal of the [2Fe-2S), ferredoxin, from, C.reinhardtii:, petF., This, protein, catalyses, the, final, reaction, in, a, pathway, which, allows, the, production, of, H(2), from, water, in, the, chloroplast, ].
This entry represents a group of bacterial proteins, including TasA from Bacillus subtilis. Microbes construct architecturally complex and ordered communities called biofilms through production of an extracellular matrix composed of an exopolysaccharide and the amyloid-like protein TasA []. TasA has the propensity to polymerize into fibres enriched in beta sheets and highly resistant to degradation or denaturation []. TasA fibres are used by B. subtilis to build a network that connects cells and may organize the rest of the components of the extracellular matrix [].
Threonine dehydratase () (TDH) catalyzes the dehydratation of threonine into alpha-ketobutarate and ammonia. In Escherichia coli and other microorganisms, two classes of TDH are known to exist. One is involvedin the biosynthesis of isoleucine, the other in hydroxamino acid catabolism.This entry describes a form of TDH that is distinct from the clades described by and . The sequences described by this entry have one copy of the threonine dehydratase C-terminal domain (). They are exclusively found in species containing the rest of the isoleucine biosynthesis pathway and which are generally lacking in members of the other two clades of threonine dehydratases. They include mitochondrial and plastid threonine dehydratases.
The overall function of the full-length Med25 is efficiently to coordinate the transcriptional activation of RAR/RXR (retinoic acid receptor/retinoic X receptor) in higher eukaryotic cells. Human Med25 consists of several domains with different binding properties, the N-terminal, VWA domain which is this one, an SD2 domain from residues 229-381, a PTOV(B) or ACID domain from 395-545, an SD2 domain from residues 564-645 and a C-terminal NR box-containing domain (646-650) from 646-747. This VWA or von Willebrand factor type A domain when bound to RAR and the histone acetyltransferase CBP is responsible for recruiting Med1 to the rest of the Mediator complex [].
Clostridial species have a layer of surface proteins surrounding their membrane. This layer is comprised of a high molecular weight protein and a low molecular weight protein.This superfamily represents a subdomain of the N-terminal domain of the Low molecular weight S layer protein (LMW SLP). Structurally, it consists of 2 alpha helices and 5 beta strands and adopts a 2-layer sandwich architecture. Within this domain, one of the beta strands is composed of C-terminal residues, while the rest of the protein is contributed to by a contiguous polypeptide chain at the N terminus [].
The NTR domain found in complement C3 is also known as the C345C domain because it occurs at the C terminus of complement C3, C4 and C5. Complement C3 plays a pivotal role in the activation of the complement systems, as all pathways (classical, alternative, and lectin) result in the processing of C3 by C3 convertase. The larger fragment, activated C3b, contains the NTR/C345C domain and binds covalently, via a reactive thioester, to cell surface carbohydrates including components of bacterial cell walls and immune aggregates. The smaller cleavage product, C3a, acts independently as a diffusible signal to mediate local inflammatory processes. The structure of C3 shows that the NTR/C345C domain is located in an exposed position relative to the rest of the molecule. The function of the domain in complement C3 is poorly understood [, ].This domain is also found in cobra venom factor, a functional analogue of human complement component C3b [].
This entry represents the Major outer membrane lipoprotein (Lpp, also known as murein lipoprotein), which controls the distance between the inner and outer membranes [, ]. This abundant protein contains lipids in its N-terminal which anchor it to the outer membrane. This is the only protein known to bind covalently to the peptidoglycan network (PGN) but it also binds it through non-covalent interactions. About one-third of the Lpp is bound to the cell wall and the rest is free in the periplasm. Lpp have a structural function mediating the interactions between the outer membrane and PGN to assure the correct distance between them and contributes to the structural and functional integrity of the cell membrane []. The role of the periplasm free Lpp remains unknown.
The biotin operon of Escherichia coli contains 5 structural genes involved in the synthesis of biotin. Transcription of the operon is regulated via one of these proteins, BirA. BirA is an asymetric protein with 3 specific domains. The ligase reaction intermediate, biotinyl-5'-AMP, is the co-repressor that triggers DNA binding by BirA.The α-helical N-terminal domain of the BirA protein has the helix-turn-helix structure of DNA-binding proteins with a central DNA recognition helix. BirA undergoes several conformational changes related to repressor function and the N-terminal DNA-binding function is connected to the rest of the molecule through a hinge which will allow relocation of the domains during the reaction []. Two repressor molecules form the operator-repressor complex, with dimer formation occuring simultaneously with DNA binding. DNA-binding may cause a conformational change which allows this co-operative interaction. In the dimer structure, the β-sheets in the central domain of each monomer are arranged side-by-side to form a single, seamless β-sheet.
L-Asparaginases () hydrolyze L-asparagine to L-aspartate and ammonia. Enzymes with asparaginase activity play an important role in the metabolism of all living organisms [, ]. Enzymes capable of converting L-asparagine to L-aspartate can be classified as bacterial-type or plant-type L-asparaginase. Bacterial-type L-asparaginase are further divided into subtypes I and II, defined by their intra-/extra-cellular localization, substrate affinity, and oligomeric form. Homologous bacterial-type L-asparaginase are found in all kingdoms of life. Furthermore, bacterial-type L-asparaginase are related to other enzymes, including:Bacterial L-glutaminase-asparaginase () [].Archaeal GatD subunit of Glu-tRNA amidotransferase (Glu-AdT) [].Mammalian lysophospholipase (), which is believed to play a majorrole in the hydrolytic degradation of lysophosphatidylcholine [].The asparaginase/glutaminase structure consists of two non-similar alpha/beta domains, each domain has three layers (alpha/beta/alpha). The first domain has mixed β-sheet of six strands with strand 6 antiparallel to the rest and left-handed crossover connection between strands 4 and 5. The second domain has parallel β-sheet of four strands.
The Streptococcus pneumoniae psaA gene encodes a protein with significant similarity to previously-reported Streptococcal proteins, SsaB (80% similarity) and FimA (92.3% similarity), from Streptococcus sanguis and Streptococcus parasanguis []. These homologues are associated with bacterial adhesion, and PsaA may play a similar role [].The SsaB protein has a putative hydrophobic 19-amino-acid signal sequence yielding a 32,620-Mr secreted protein []. SsaB is hydrophilic and appears not to have a hydrophobic membrane anchor in its C-terminal region. A high degree of similarity exists between S. sanguis ssaB and type 1 fimbrial genes []. Comparison of the gene products reveals close similarity of the two proteins. It is thought that ssaB adhesion may play a role in oral colonisation by binding either to a receptor on saliva or to a receptor on Actinomyces.This sub-family is described by from conserved regions spanning the full alignmentlength, focusing on those sections that characterise the adhesin Bprecursors but distinguish them from the rest of the adhesin family.
The translationally controlled tumor proteins (TCTPs, such as p21, p23 and histamine releasing factor (HRF)) are a highly conserved and abundantly expressed family of eukaryotic proteins that are implicated in a variety of cellular functions, including microtubule stabilization, cell cycle, apoptosis, and cytokine release. TCTP is ubiquitously expressed in all eukaryotic organisms from protozoa such as Plasmodium sp. to plants and mammals [, , , ].The TCTP domain structure comprises four β-sheets, designated A-D, and three main helices, designated H1-H3, connected in a complex topology. A central feature of the structure is the four-stranded sheet A, against one face of which packs the three-stranded sheet B and the small helix H1. Helix H3 packs against part of the opposite face of sheet A. Helix H2 packs against helix H3 (forming an α-helical hairpin). The final major structural feature is the two-stranded sheet C, which protrudes from the core globular structure formed by the rest of the domain [].This entry represents the TCTP domain.
There are three major pilin subunits that form the polymeric backbone of the pilin from S. pneumoniae, constructed of three Ig-like, CnaB, domains along with a crucial N-terminal domain, D1. The three IG-like domains are stabilised by internal Lys-Asn isopeptdie bonds, but this N-terminal domain makes few contact with the rest of the molecule due to the different orientation of its G β-strand. Strand G of D1 also carries the YPKN motif that provides the essential Lys residue for the sortase-mediated intermolecular linkages along the pilus shaft. Gram-positive pili are formed from a single chain of covalently linked subunit proteins (pilins), usually comprising an adhesin at the distal tip, a major pilin that forms the polymer shaft and a minor pilin that mediates cell wall anchoring at the base [].
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].This entry represents the probable glycine dehydrogenase (decarboxylating) subunit 2 from prokaryotes.
The P protein is part of the glycine decarboxylase multienzyme complex (GDC), also annotated as glycine cleavage system or glycine synthase. GDC consists of four proteins P, H, L and T []. The P protein () binds the alpha-amino group of glycine through its pyridoxal phosphate cofactor, carbon dioxide is released and the remaining methylamin moiety is then transferred to the lipoamide cofactor of the H protein. The reaction catalysed by this protein is:Glycine + lipoylprotein = S-aminomethyldihydrolipoylprotein + CO2 The subunit composition of glycine cleavage system P proteins have been classified into two types. Those from eukaryotes and some of the P proteins from prokaryotes (e.g. Escherichia coli) are in the homodimeric form. The rest of those from prokaryotes are heterotetrameric, with two different subunits which, based on sequence similarities, correspond respectively to the N and C-terminal halves of the eukaryotic subunit [].This entry represents the P protein homodimeric subfamily, which is found in eukaryotes and some prokaryotes, such as E. coli.
MutT is a small bacterial protein (~12-15Kd) involved in the GO system []responsible for removing an oxidatively damaged form of guanine (8-hydroxy-guanine or 7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool. 8-oxo-dGTP is inserted opposite dA and dC residues of template DNA with near equal efficiency, leading to A-T to G-C transversions. MutT specifically degrades 8-oxo-dGTP to the monophosphate, with the concomitant release of pyrophosphate. A short conserved N-terminal region of mutT (designated the MutT domain) is also found in a variety of other prokaryotic, viral and eukaryotic proteins [, ,, ].The generic name 'NUDIX hydrolases' (NUcleoside DIphosphate linked to some other moiety X) has been coined for this domain superfamily []. The superfamily can be divided into a number of subgroups, of which MutT anti-mutagenic activity represents only one type; most of the rest hydrolyse diverse nucleoside diphosphate derivatives (including ADP-ribose, GDP-mannose, TDP-glucose, NADH, UDP-sugars, dNTP and NTP).
This domain superfamily is found in apolipoprotein CII (apoC-II). ApoC-II is a surface constituent of plasma lipoproteins and the activator for lipoprotein lipase (LPL). It is therefore central for lipid transport in blood. Lipoprotein lipase is a key enzyme in the regulation of triglyceride levels in human serum []. It is the C-terminal helix of apoCII that is responsible for the activation of LPL []. The active peptide of apoC-II occurs at residues 44-79 and has been shown to reverse the symptoms of genetic apoC-II deficiency in a human subject [].Micellar SDS, a commonly used mimetic of the lipoprotein surface, inhibits the aggregation of apoC-II and induces a stable structure containing approximately 60% α-helix. The first 12 residues of apoC-II are structurally heterogeneous but the rest of the protein forms a predominantly helical structure [].
Apolipoprotein CII (apoC-II) is a surface constituent of plasma lipoproteins and the activator for lipoprotein lipase (LPL). It is therefore central for lipid transport in blood. Lipoprotein lipase is a key enzyme in the regulation of triglyceride levels in human serum []. It is the C-terminal helix of apoC-II that is responsible for the activation of LPL []. The active peptide of apoC-II occurs at residues 44-79 and has been shown to reverse the symptoms of genetic apoC-II deficiency in a human subject [].Micellar SDS, a commonly used mimetic of the lipoprotein surface, inhibits the aggregation of apoC-II and induces a stable structure containing approximately 60% α-helix. The first 12 residues of apoC-II are structurally heterogeneous but the rest of the protein forms a predominantly helical structure [].
This family consists of examples of the threonine biosynthesis (Thr) operon leader peptide, also called the Thr operon attenuator. The small gene for this peptide is often missed in genome annotation. It should be looked for in genomes of the proteobacteria, immediately upstream of genes for threonine biosynthesis, typically aspartokinase I/homoserine dehydrogenase, homoserine kinase, and threonine synthase. Transcription of the rest of the Thr operon is attenuated (mostly turned off) unless the ribosome pauses during a stretch of the leader sequence rich in both Ile (made from Thr) and in Thr itself because of the scarcity of those amino acids at the time. The leader peptide itself, once made, may have no role other than to be degraded. Similar systems exist for some other amino acid biosynthetic operons, such as Trp.
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [, ]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble []. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. This entry contains Utp14, a large ribonuclear protein associated with snoRNA U3 [].
This entry represents a domain consisting of twelve helices that fold into a compact structure that contains the overall structural scaffold observed in other regulator of G protein signalling (RGS) proteins and three additional helical elements that pack closely to it. Helices 1-9 comprise the RGS fold, in which helices 4-7 form a classic antiparallel bundle adjacent to the other helices. Like other RGS structures, helices 7 and 8 span the length of the folded domain and form essentially one continuous helix with a kink in the middle. Helices 10-12 form an apparently stable C-terminal extension of the structural domain, and although other RGS proteins lack this structure, these elements are intimately associated with the rest of the structural framework by hydrophobic interactions. This domain binds to active G-alpha proteins, promoting GTP hydrolysis by the alpha subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signalling pathways []. This RGS-like domain is found in Rho guanine nucleotide exchange factors (RhoGEF) such as Pdz-RhoGEF []and p115RhoGEF [].
The SAGA (Spt-Ada-Gcn5-acetyltransferase) complex performs multiple functions in transcription activation including deubiquitinating histone H2B, which is mediated by a subcomplex called the deubiquitinating module (DUBm). The yeast DUBm comprises a catalytic subunit, Ubp8, and three additional subunits, Sgf11, Sus1 and Sgf73, all of which are required for DUBm activity. A portion of the non-globular Sgf73 subunit lies between the Ubp8 catalytic domain and the zinc finger (Znf)-UBP domain and has been proposed to contribute to deubiquitinating activity by maintaining the catalytic domain in an active conformation. Sgf73 contributes to maintaining both the organization and ubiquitin-binding conformation of Ubp8, thereby contributing to overall DUBm activity. This domain is a Sgf73 fragment in the DUB module. It is a zinc finger (Znf) domain whose integrity is essential for the incorporation of this subunit into DUBm as well as for the catalytic activity of Ubp8, as either a short deletion or point mutations in Sgf73 zinc-coordinating residues disrupt the association of Sgf73 with the rest of the DUBm [, , , ].
The biotin operon of Escherichia coli contains 5 structural genes involved in the synthesis of biotin. Transcription of the operon is regulated via one of these proteins, the biotin ligase BirA. BirA is an asymetric protein with 3 specific domains - an N-terminal DNA-binding domain, a central catalytic domain and a C-terminal of unknown function. The ligase reaction intermediate, biotinyl-5'-AMP, is the co-repressor that triggers DNA binding by BirA.The α-helical N-terminal domain of the BirA protein has the helix-turn-helix structure of DNA-binding proteins with a central DNA recognition helix. BirA undergoes several conformational changes related to repressor function and the N-terminal DNA-binding function is connected to the rest of the molecule through a hinge which will allow relocation of the domains during the reaction []. Biotin-binding causes a large structural change thought to facilitate ATP-binding.Two repressor molecules form the operator-repressor complex, with dimer formation occuring simultaneously with DNA binding. DNA-binding may also cause a conformational change which allows this co-operative interaction. In the dimer structure, the β-sheets in the central domain of each monomer are arranged side-by-side to form a single, seamless β-sheet. The apparent orthologs among the eukaryotes are larger proteins that contain a domain with high sequence homology to BirA.
The p53 tumour suppressor [, , , , ]is a protein found in increased amounts in a wide variety of transformed cells. It is also detectable in many proliferating non-transformed cells, but it is undetectable or present at low levels in resting cells. It is frequently mutated or inactivated in many types of cancer. p53 seems to act as a tumour suppressor in some, but probably not all, tumour types. p53 has been implicated in cell cycle regulation, particularly in the monitoring of genomic DNA integrity prior to replication; for this reason it has been dubbed `guardian of the genome'. p53 is a sequence-specific DNA-binding protein and transcription factor. The structure of p53 comprises 4 domains: an N-terminal transactivation domain; a central DNA-binding domain; an oligomerisation domain; and a C-terminal, basic, regulatory domain [, ]. The structure of the oligomerisation domain consists of a dimer of dimers, each dimer consisting of 2 anti-parallel α-helices and an anti-parallel β-sheet. The sheets lie on opposite sides of the tetramer and the helices form an unusual 4-helix bundle [, ]. While the majority of p53 mutations found in human cancers are located in the DNA-binding domain, some are also found in the oligomerisation domain.This entry represents the C-terminal domain of Drosophila transcription factor p53. While the rest of the protein is quite conserved between the different transcription factors such as p53 and p73, the C-terminal domain is highly divergent. The Drosophila p53 structure is characterised by an additional N-terminal β-strand and a C-terminal helix [].
The p53 tumour suppressor [, , , , ]is a protein found in increased amounts in a wide variety of transformed cells. It is also detectable in many proliferating non-transformed cells, but it is undetectable or present at low levels in resting cells. It is frequently mutated or inactivated in many types of cancer. p53 seems to act as a tumour suppressor in some, but probably not all, tumour types. p53 has been implicated in cell cycle regulation, particularly in the monitoring of genomic DNA integrity prior to replication; for this reason it has been dubbed `guardian of the genome'. p53 is a sequence-specific DNA-binding protein and transcription factor. The structure of p53 comprises 4 domains: an N-terminal transactivation domain; a central DNA-binding domain; an oligomerisation domain; and a C-terminal, basic, regulatory domain [, ]. The structure of the oligomerisation domain consists of a dimer of dimers, each dimer consisting of 2 anti-parallel α-helices and an anti-parallel β-sheet. The sheets lie on opposite sides of the tetramer and the helices form an unusual 4-helix bundle [, ]. While the majority of p53 mutations found in human cancers are located in the DNA-binding domain, some are also found in the oligomerisation domain.This entry represents the C-terminal domain of Drosophila transcription factor p53. While the rest of the protein is quite conserved between the different transcription factors such as p53 and p73, the C-terminal domain is highly divergent. The Drosophila p53 structure is characterised by an additional N-terminal β-strand and a C-terminal helix [].
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [, ]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble []. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. This entry contains Utp11, a large ribonuclear protein that associates with snoRNA U3 [].
MutT is a small bacterial protein (~12-15Kd) involved in the GO system []responsible for removing an oxidatively damaged form of guanine (8-hydroxy-guanine or 7,8-dihydro-8-oxoguanine) from DNA and the nucleotide pool.8-oxo-dGTP is inserted opposite dA and dC residues of template DNA with near equal efficiency, leading to A.T to G.C transversions. MutTspecifically degrades 8-oxo-dGTP to the monophosphate, with the concomitantrelease of pyrophosphate. A short conserved N-terminal region of mutT (designated the MutT domain) is also found in a variety of otherprokaryotic, viral and eukaryotic proteins [, , , ].The generic name `NUDIX hydrolases' (NUcleoside DIphosphate linkedto some other moiety X) has been coined for this domain family []. Thefamily can be divided into a number of subgroups, of which MutT anti-mutagenic activity represents only one type; most of the rest hydrolysediverse nucleoside diphosphate derivatives (including ADP-ribose, GDP-mannose, TDP-glucose, NADH, UDP-sugars, dNTP and NTP).This signature covers the core region of the NUDIX domain and contains four conserved glutamate residues []. The region spanned by this signature could be part of the active centre of a family of pyrophosphate-releasing NTPases.
A large ribonuclear protein complex is requiredfor the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [, ]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble []. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. Utp21 is a component of the SSU processome, which is required for pre-18S rRNA processing. It interacts with Utp18 [].
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. Thismodified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [].This superfamily represents the domain 2 found in diphthamide synthesis DPH1/DPH2 enzymes.
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangement resemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [].This superfamily represents the domain 1 found in diphthamide synthesis DPH1/DPH2 enzymes.
Diphthamide is the name given to a unique post-translationally modified histidine residue in archaeal and eukaryotic translation elongation factor 2. This modified histidine is target of diphtheria toxin, which inhibits eukaryotic protein synthesis by ADP-ribosylating diphthamide in EF2 [].The diphthamide synthesis DPH1/DPH2 enzymes which catalyse the first step in diphthamide biosynthesis. Archaeal DPHs are more similar to eukaryotic DPH1 than to DPH2 [].Available structural information on PhDph2 reveals that this enzyme is a homodimer and that each monomer comprises three domains which share the same overall fold. The basic domain fold is a four-stranded parallel β-sheet with three flanking α-helices (or two α-helices and one 3(10) helix in the case of domain 2). The two β-sheets in domain 1 and 2 each contain an additional β-strand that is antiparallel to the rest of the β-sheet. Domains 2 and 3 have two additional α-helices. Domain 1 of one monomer and domain 3 of the adjacent monomer form the dimer interface, creating an extended nine-stranded β-sheet. The domain folds and their arrangementresemble the structure of quinolinate synthase but the orientations of the domains with respect to each other are different in the two enzymes. Three conserved cysteine residues (Cys59, Cys163 and Cys287), each coming from a different structural domain, are clustered together in the centre of the PhDph2 monomers. All three cysteine residues are conserved in eukaryotic DPH1s. The first and third cysteine residues are conserved in eukaryotic DPH2s [].This superfamily represents the domain 3 found in diphthamide synthesis DPH1/DPH2 enzymes.
Peptidase S24 LexA-like proteins are involved in the SOS response leading to the repair of single-stranded DNA within the bacterial cell []. Proteins containing this domain includes LexA, MucA and UmuD. LexA () is the repressor of genes in the cellular SOS response to DNA damage []. The LexA-like proteins contain two-domains: an N-terminal DNA binding domain and a C-terminal domain (CTD) that provides LexA dimerization as well as cleavage activity []. They undergo autolysis, cleaving at an Ala-Gly or a Cys-Gly bond, separating the DNA-binding domain from the rest of the protein []. The LexA, UmuD and MucD proteins interact with RecA, which activates self cleavage either derepressing transcription in the case of LexA []or activating the lesion-bypass polymerase in the case of UmuD and MucA. UmuD'2, is the homodimeric component of DNA pol V, which is produced from UmuD by RecA-facilitated self-cleavage. The first 24 N-terminal residues of UmuD are removed; UmuD'2 is a DNA lesion bypass polymerase [, ]. MucA [, ], like UmuD, is a plasmid encoded a DNA polymerase (pol RI) which is converted into the active lesion-bypass polymerase by a self-cleavage reaction involving RecA [].
This entry represents a domain superfamily found in Bacteriophage T4, Gp12. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.This region is occasionally found in conjunction with . Most of the proteins appear to be phage tail proteins; however some appear to be involved in other processes. For instance the RhiB protein () from Rhizobium leguminosarum may be involved in plant-microbe interactions []. A related protein, microcystin related protein (MrpB, ) is involved in the pathogenicity of Microcystis aeruginosa. The finding of this family in a structural component of the phage tail fibre baseplate () suggests that its function is structural rather than enzymatic. Structural studies show this region consists of a helix and a loop []and three β-strands. This alignment does not catch the third strand as it is separated from the rest of the structure by around 100 residues. This strand is conserved in homologues but the intervening sequence is not. Much of the function of appears to reside in this intervening region. In the tertiary structure of the phage baseplate this domain forms part of the collar and may bind SO4. The long unconserved region maybe due to domain swapping in and out of a loop or due to rapid evolution.
Transcription initiation factor TFIID is a multimeric protein complex thatplays a central role in mediating promoter responses to various activatorsand repressors. The complex includes TATA binding protein (TBP) and variousTBP-associated factors (TAFS). TFIID is a bona fide RNA polymerase II-specificTATA-binding protein-associated factor (TAF) and is essential for viability []. This entry represents one of the TAFs, TAF10.TFIID acts to nucleate the transcription complex, recruiting the rest ofthe factors through a direct interaction with TFIIB. The TBP subunit of TFIID is sufficient for TATA-element binding and TFIIB interaction, and can support basal transcription. The protein belongs to the TAF2H family.TAF10 is part of other transcription regulatory multiprotein complexes (e.g., SAGA, TBP-free TAF-containing complex [TFTC], STAGA, and PCAF/GCN5). Several TAFs interact via histone-fold motifs. The histone fold (HFD) is the interaction motif involved in heterodimerization of the core histones and their assembly into nucleosome octamer. The minimal HFD contains three α-helices linked by two loops. The HFD is found in core histones, TAFs and many other transcription factors. Five HF-containing TAF pairs have been described in TFIID: TAF6-TAF9, TAF4-TAF12, TAF11-TAF13, TAF8-TAF10 and TAF3-TAF10 [, , ].
Ryanodine receptors are involved in communication between transverse-tubulesand the sarcoplamic reticulum of cardiac and skeletal muscle. The proteinsfunction as a Ca2+-release channels following depolarisation of transverse-tubules []. The function is modulated by Ca2+, Mg2+, ATP and calmodulin.Deficiency in the ryanodine receptor may be the cause of malignanthyperthermia (MH) and of central core disease of muscle (CCD) []. MH isan autosomal dominant disorder of skeletal muscle and is a principalcause of death due to anaesthesia.Calcium release activity of the receptors resides in the C-terminal regionof the protein, the remaining part of the molecule forming a 'foot'structure that spans the junctional gap between the sarcoplamic reticulumand the transverse-tubule. The foot structure may interact with thecytoplasmic region of the dihydropyridine receptor.Analysis of the sequence reveals 10 potential transmembrane (TM) regionsin the C-terminal fifth of the molecule and 2 further potential TM regionsnearer to the centre []. These may contribute to the formation of the Ca2+conducting pore. The rest of the sequence is hydrophilic, and presumablyconstitutes the cytoplasmic domain of the protein.
This entry is represented by a domain found in Bacteriophage T4, Gp12. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.This region is occasionally found in conjunction with . Most of the proteins appear to be phage tail proteins; however some appear to be involved in other processes. For instance the RhiB protein () from Rhizobium leguminosarum may be involved in plant-microbe interactions []. A related protein, microcystin related protein (MrpB, ) is involved in the pathogenicity of Microcystis aeruginosa. The finding of this family in a structural component of the phage tail fibre baseplate () suggests that its function is structural rather than enzymatic. Structural studies show this region consists of a helix and a loop []and three β-strands. This alignment does not catch the third strand as it is separated from the rest of the structure by around 100 residues. This strand is conserved in homologues but the intervening sequence is not. Much ofthe function of appears to reside in this intervening region. In the tertiary structure of the phage baseplate this domain forms part of the collar and may bind SO4. The long unconserved region maybe due to domain swapping in and out of a loop or due to rapid evolution.
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics []. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets [, ]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.This entry represents the entirehaemagglutinin protein (HA0) consisting of both the HA1 and HA2 regions, as found in influenza A and B viruses.
The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains: N-terminal domain (amidotransferase domain ), central (consisting of and the FMN-binding domain ), and C-terminal domain. This family of sequences represent a fusion of the N-terminal (amidotransferase) domain and the C-terminal structural domain.The stand-alone forms of the three domains (and for domains 1 and 2), as well as partial fusions, occur in the archaeal type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard"bacterial enzyme [].Originally, only the ORF encoding the central domain of GOGAT has been recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some miss-annotations []. This has led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs [].Glutamate synthase is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channelling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation []. GOGAT is a multifunctional enzyme that performs L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor [].There are four classes of GOGAT [, ]: 1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT, ). This standard bacterial NADPH-GOGAT is composed of a large subunit and a small subunit.2. Ferredoxin-dependent form in cyanobacteria and plants (Fd-GOGAT, ) displays a single-subunit structure corresponding to the large bacterial subunit.3. Pyridine-linked form in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT, ) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits ().4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit [, ](, ), and to the small subunit.
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previousinfluenza strains, accounting for recurrent influenza epidemics []. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets [, ]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.This entry represents haemagglutinin found in influenza virus B.
The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT, GltS) consists of three domains. This entry represents a stand-alone version of the N-terminal amidotransferase domain that is found in archaeal GOGAT, where the large subunit is represented by three separate proteins corresponding to the three domains of the "standard"bacterial enzyme []. Similar organisation of GOGAT with stand-alone domains has been found in some bacteria (e.g., Sinorhizobium meliloti and Thermotoga maritima), but its function is not clear in those organisms where the "standard"(integrated) bacterial form is also present (e.g., Sinorhizobium meliloti).The amidotransferase domain of the bacterial GOGAT is characterised by a four layer alpha/beta/beta/alpha architecture []and contains the typical catalytic centre. The N-terminal Cys-1 catalyses the hydrolysis of L-glutamine generating ammonia and the first molecule of L-glutamate [].Originally, only the ORF encoding the central domain of GOGAT was recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some misannotations []. This led to speculation that the archaeal form of the GOGAT large subunit was the ancestral minimal form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs [].Glutamate synthase is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channeling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation []. GOGAT is a multifunctional enzyme that functions through three distinct active centres carrying out multiple reaction steps: L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor [].
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics []. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets [, ]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.This entry represents the stalk segment of haemagglutinin in influenza C virus. It forms a coiled coil structure [].
Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation which is usually zinc, but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophillic role. Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site []. The HEXXH motif is relatively common, but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases [].This family is a subset of the members of the zinc metallopeptidases belonging to MEROPS peptidase family M1 (aminopeptidase N, clan MA), with a single member characterised in Streptomyces lividans: aminopeptidase G []. The rest of the members of this family are identified as aminopeptidase N of the actinomycete-type. The spectrum of activity may differ somewhat from the aminopeptidase N clade of Escherichia coli and most other proteobacteria, which are well separated phylogenetically within the M1 family.
This entry represents a conserved unique core sequence shared by large numbers of proteins. It is occasionally found in the Archaea, including Methanosarcina barkeri) but commonly found in the bacteria and eukaryotes. Most fall into two large classes. One class consists of long proteins in which two classes of repeats are abundant: an FG-GAP repeat () class, and an RHS repeat () or YD repeat (). This class includes secreted bacterial insecticidal toxins and intercellular signalling proteins such as the teneurins in animals. The other class consists of uncharacterised proteins shorter than 400 amino acids, where this core domain of about 75 amino acids tends to occur in the N-terminal half. Over twenty such proteins are found in Pseudomonas putida alone; little sequence similarity or repeat structure is found among these proteins outside of this domain. The C protein of bacterial ABC toxin complexes has a conserved RHS-repeat-containing N-terminal region and a variable C-terminal region, which is the main cytotoxic component. The C protein forms a large hollow shell structure with the B protein encapsulating the divergent C-terminal domain. An explanation for this structure could be that it allows the toxic load to remain sequestered until a change in pH triggers its release. The RHS repeat-associated core domain forms a short strip of β-sheets that spirals inwards the shell structure, forming a plug at the C end of the shell. The RHS core domain also functions as a self-cleaving protease, cleaving the C-terminal domain from the rest of the protein [].YD repeats are found in many bacterial and eukaryotic proteins, notably in the extracellular domains of teneurin proteins, which are developmental signalling proteins conserved from flies to mammals []. It has been suggested that RHS and YD repeats may represent the same conserved structural motif contributing to a similar shell structure that encapsulates the teneurin C-terminal region [].
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [, ]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble []. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. This domain is found at the C terminus of proteins containing WD40 repeats. These proteins are part of the U3 ribonucleoprotein. In yeast, these proteins are called Utp5, Utp1 or Pwp2, Utp12 or DIP2 . They interact with snoRNA U3 and with MPP10 []. Pwp2 is an essential Saccharomyces cerevisiae (Baker's yeast) protein involved in cell separation.
Potyviruses form one of the most numerous groups of plant viruses and are a major cause of crop loss worldwide. The helper-component proteinase (HC-Pro) is an indispensable, multifunctional protein of members of the genus Potyvirus and other viruses of the family Potyviridae. It is directly involved in diverse steps of viral infection, such as aphid plant-to-plant transmission, polyprotein processing, and suppression of host antiviral RNA silencing. HC-Pro is generally divided into three functional domains: a N-terminal domain, a central region, and a cysteine protease domain (CPD) in the C-terminal region. The HC-Pro CPD domain has a protease activity that autocatalytically cleaves a Gly-Gly dipeptide at its own C terminus to release HC-Pro from the rest of the viral polyprotein. Cysteine and histidine residues form the catalytic dyad at the active site. The HC-Pro CPD domain constitutes the peptidase family C6 of the CA clan [].The HC-Pro CPD domain adopts a compact oval-shaped alpha/beta fold. The secondary structure elements include four α-helices (alpha1-alpha4) and two short β-strands (beta1 and beta2) arranged in the order alpha1-alpha2-alpha3-beta1-beta2-alpha4. In addition, two 3(10) helices are located between alpha3 and beta1 and downstream of alpha4. The four helices form a helix bundle packed against one face of a short β-hairpin formed by strands beta1 and beta2. The catalytic residue Cys is located at the N terminus of helix alpha1, and the other catalytic residue His is located on strand beta2. The substrate binding cleft is lined by the loop connecting helices alpha2 and alpha3 and the N-terminal region of helix alpha1 on one side and by strand beta2 on the other side [].This superfamily represents the CPD domain of the HC-Pro protein.
The CRISPR-Cas system is a prokaryotic defense mechanism against foreign genetic elements. The key elements of this defense system are the Cas proteins and the CRISPR RNA. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) are a family of DNA direct repeats separated by regularly sized non-repetitive spacer sequences that are found in most bacterial and archaeal genomes []. CRISPRs appear to provide acquired resistance against mobile genetic elements (viruses, transposable elements and conjugative plasmids). CRISPR clusters contain sequences complementary to antecedent mobile elements and target invading nucleic acids. CRISPR clusters are transcribed and processed into CRISPR RNA (crRNA).The defense reaction is divided into three stages. In the adaptation stage, the invader DNA is cleaved, and a piece of it is selected to be integrated as a new spacer into the CRISPR locus, where it is stored as an identity tag for future attacks by this invader. During the second stage (the expression stage), the CRISPR RNA (pre-crRNA) is transcribed and subsequently processed into the mature crRNAs. In the third stage (the interference stage), Cas proteins, together with crRNAs, identify and degrade the invader [, , ].The CRISPR-Cas systems have been sorted into three major classes. In CRISPR-Cas types I and III, the mature crRNA is generally generated by a member of the Cas6 protein family. Whereas in system III the Cas6 protein acts alone, in some class I systems it is part of a complex of Cas proteins known as Cascade (CRISPR-associated complex for antiviral defense). The Cas6 protein is an endoribonuclease necessary for crRNA production whereas the additional Cas proteins that form the Cascade complex are needed for crRNA stability []. This entry represents a minor class of Cas proteins, known as Cas8b [], found in at least five prokaryotic genomes: Methanosarcina mazei, Sulfurihydrogenibium azorense, Thermotoga maritima, Carboxydothermus hydrogenoformans, and Dictyoglomus thermophilum, the first of which is archaeal while the rest are bacterial []. Cas8b is a large subunit of the Type-I-B Cascade complex found in Clostridium thermocellum and Methanococcus maripaludis [].
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics []. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets [, ]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.This superfamily represents a subdomain of the HA1 peptide that occurs following HA0 cleavage. This subdomain has an alpha/beta structure.
This entry represents the CPD domain of the HC-Pro protein. Potyviruses form one of the most numerous groups of plant viruses and are a major cause of crop loss worldwide. The helper-component proteinase (HC-Pro) is an indispensable, multifunctional protein of members of the genus Potyvirus and other viruses of the family Potyviridae. It is directly involved in diverse steps of viral infection, such as aphid plant-to-plant transmission, polyprotein processing, and suppression of host antiviral RNA silencing. HC-Pro is generally divided into three functional domains: a N-terminal domain, a central region, and a cysteine protease domain (CPD) in the C-terminal region. The HC-Pro CPD domain has a protease activity that autocatalytically cleaves a Gly-Gly dipeptide at its own C terminus to release HC-Pro from the rest of the viral polyprotein. Cysteine and histidine residues form the catalytic dyad at the active site. The HC-Pro CPD domain constitutes the peptidase family C6 of the CA clan [].The HC-Pro CPD domain adopts a compact oval-shaped alpha/beta fold. The secondary structure elements include four α-helices (alpha1-alpha4) and two short β-strands (beta1 and beta2) arranged in the order alpha1-alpha2-alpha3-beta1-beta2-alpha4. In addition, two 3(10) helices are located between alpha3 and beta1 and downstream of alpha4. The four helices form a helix bundle packed against one face of a short β-hairpin formed by strands beta1 and beta2. The catalytic residue Cys is located at the N terminus of helix alpha1, and the other catalytic residue His is located on strand beta2. The substrate binding cleft is lined by the loop connecting helices alpha2 and alpha3 and the N-terminal region of helix alpha1 on one side and by strand beta2 on the other side [].
Glutamate synthase (GOGAT, GltS) is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate (2-OG) and L-glutamine via intramolecular channeling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation []. GOGAT is a multifunctional enzyme that functions through three distinct active centres carrying out multiple reaction steps: L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor [].There are four classes of glutamate synthase (GOGAT) [], []:1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT, ). This standard bacterial NADPH-GOGAT (GltS) is composed of a large (alpha, GltB) subunit, and a small (beta, GltD) subunit.2. Ferredoxin-dependent GOGAT in cyanobacteria and plants (Fd-GOGAT from photosynthetic cells, ) displays a single-subunit structure corresponding to the large bacterial subunit.3. Pyridine-linked GOGAT in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT, ) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits. 4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit and to the small subunit.The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains: the N-terminal amidotransferase domain (), the central domain, and the C-terminal domain (). This entry represents a stand-alone version of the central domain. The stand-alone form occurs in the archaeal-type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard"bacterial enzyme [].The second (central) domain of the bacterial GOGAT large subunit consists of a linker domain and the FMN-binding domain (). The FMN-binding domain has a beta/alpha barrel topology. In this domain, the 2-iminoglutarate intermediate, formed upon the addition of ammonia onto 2-oxoglutarate, is reduced by the FMN cofactor producing the second molecule of L-glutamate []. This domain also contains the enzyme 3Fe-4S cluster [].All members of this entry contain the FMN-binding domain. However, they lack the linker domain, and some have 1-3 copies of (4Fe-4S binding domain) in the N-terminal region.Originally, only the ORF encoding the central domain of GOGAT was recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some misannotations []. This led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs [].
Rodent urinary proteins (mouse major urinary proteins or MUPs and rat alpha-2u globulins) are the major protein components of rodent urine and transport pheromones [].Rodent urine contains an unusually large amount of protein. The major site of MUP synthesis is the liver; the protein is secreted by the liver into serum, where it circulates at relatively low levels before being rapidly filteredby the kidney and excreted.The sex-dependent expression of MUP (adult male mice secrete 5-20 times as much MUP as do females) and its ability to bind a number of odorant molecules is consistent with the suggestion that MUP acts as a pheromonetransporter; the protein may be excreted into the urine carrying a boundpheromone, which is released as the urine dries and the protein denatures.The crystal structure of MUP has been solved []and is known to be a member of the lipocalin family. Alpha-2u-globulin, a close homologue of MUP, accounts for 30-50% of totalexcreted protein in adult male rat urine. As its electrophoretic mobilityis similar to that of serum a2 globulin, it was named 'alpha-2u-globulin',the subscript 'u' denoting its origin in urine. Alpha-2u-globulin is secreted into the plasma by a number of tissues, where it circulates beforefiltration through the kidney; between 20 and 50% is reabsorbed by theproximal tubule of the nephron, the rest being excreted. Although the exactphysiological role of alpha-2u-globulin is unclear, there is circumstantialevidence that it functions in pheromone transport. This is consistent withits observed binding properties, its close similarity with MUP and the knownproperties of male rat urine.Some of the proteins in this family are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature SubcommitteeKing T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E.,Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed ofthe first three letters of the genus; a space; the first letter of thespecies name; a space and an arabic number. In the event that two speciesnames have identical designations, they are discriminated from one anotherby adding one or more letters (as necessary) to each species designation.The allergens in this family include allergens with the following designations: Mus m 1 and Rat m 1.
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents the P2Y1 receptor, it is activated by adenine nucleotides and not by uracil nucleotides. Avian P2Y1 receptors are activated by ATP and ADP [, ], whereas mammalian P2Y1 receptors are potently activated mainly by ADP and related diphosphate analogues [, , ]. The P2Y1 receptor couples mainly Gq/11, and is expressed in the heart, skeletal muscle, aortic endothelium, pancreas, spleen, brain and spinal cord [, ]. It mediates muscle relaxation []and the release of endothelium-derived nitric oxide []. P2Y1 is also expressed in blood platelets [, ]and plays a crucial role in ADP-induced platelet aggregation [].
Haemagglutinin (HA) is one of two main surface fusion glycoproteins embedded in the envelope of influenza viruses, the other being neuraminidase (NA). There are sixteen known HA subtypes (H1-H16) and nine NA subtypes (N1-N9), which together are used to classify influenza viruses (e.g. H5N1). The antigenic variations in HA and NA enable the virus to evade host antibodies made to previous influenza strains, accounting for recurrent influenza epidemics []. The HA glycoprotein is present in the viral membrane as a single polypeptide (HA0), which must be cleaved by the host's trypsin-like proteases to produce two peptides (HA1 and HA2) in order for the virus to be infectious. Once HA0 is cleaved, the newly exposed N-terminal of the HA2 peptide then acts to fuse the viral envelope to the cellular membrane of the host cell, which allows the viral negative-stranded RNA to infect the host cell. The type of host protease can influence the infectivity and pathogenicity of the virus.The haemagglutinin glycoprotein is a trimer containing three structurally distinct regions: a globular head consisting of anti-parallel β-sheets that form a β-sandwich with a jelly-roll fold (contains the receptor binding site and the HA1/HA2 cleavage site); a triple-stranded, coiled-coil, α-helical stalk; and a globular foot composed of anti-parallel β-sheets [, ]. Each monomer consists of an intact HA0 polypeptide with the HA1 and HA2 regions linked by disulphide bonds. The N terminus of HA1 provides the central strand in the 5-stranded globular foot, while the rest of the HA1 chain makes its way to the 8-stranded globular head. HA2 provides two alpha helices, which form part of the triple-stranded coiled-coil that stabilises the trimer, its C terminus providing the remaining strands of the 5-stranded globular foot.This entry represents haemagglutinin from influenza virus A. The influenza A HAs can be divided into group 1 encompassing H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17, and H18, and group 2 including H3, H4, H7, H10, H14, and H15 subtypes []. This entry also includes HA from Bat-derived influenza-like viruses H17N10 () [].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents P2Y4 receptor, which is expressed in the placenta, the lung, vascular smooth muscle [, , ]and enteric glial cells [, ]. The receptor can couple to both Gi and Gq/11. In cells stably expressing the receptor, UTP has been shown to stimulate the formation of inositol phosphates with maximal effect [, , ], while ATP behaves as a partial agonist [], and ADP is almost inactive []. In guinea pig gallbladder smooth musclecells, P2Y4 activation is followed by phospholipase A2 and COX-1 stimulation []. In human HaCaT keratinocytes, UTP acting on the P2Y4 receptor stimulates ERK1/2 phosphorylation, which in turn leads to IL-6 production []. P2Y4-mediated ERK1/2 activation has also been detected in human midbrain-derived neuroprogenitor cells []. The P2Y4 receptor has been shown to regulate chloride epithelial transport [, ].
The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains: N-terminal domain (amidotransferase domain) or related (in archaeal GOGAT), central domain and the FMN-binding domain, and C-terminal domain. This family represents a stand-alone form of the C-terminal domain. The stand-alone form occurs in the archaeal type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard"bacterial enzyme []. Similar organisation of GOGAT with stand-alone domains has been found in some bacteria (e.g., members from Sinorhizobium meliloti, Thermotoga maritima), but its function is not clear in those organisms where the "standard"bacterial form is also present (e.g., Sinorhizobium meliloti).This domain is also called the GXGXG structural domain, containing repeated sequence motif G-XX-G-XXX-G). It has a right-handed β-helix topology composing seven β-helical turns. It does not have a direct function in glutamate synthase activity but rather a structural function through extensive interactions with the amidotransferase and FMN-binding domains [, ].Originally, only the ORF encoding the central domain of GOGAT has been recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some miss-annotations []. This has led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs [].Glutamate synthase (GOGAT, GltS) is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate and L-glutamine via intramolecular channelling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation []. GOGAT is a multifunctional enzyme that performs L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor [].There are four classes of GOGAT [, ]: 1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT, ). This standard bacterial NADPH-GOGAT is composed of a large (alpha, GltB) subunit and a small (beta, GltD) subunit.2. Ferredoxin-dependent form in cyanobacteria and plants (Fd-GOGAT, ) displays a single-subunit structure corresponding to the large bacterial subunit.3. Pyridine-linked form in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT, ) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits ().4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit [, ](, , ), and to the small subunit.
This entry represents the CRIB domain. Many putative downstream effectors of the small GTPases Cdc42 and Rac contain a GTPase binding domain (GBD), also called p21 binding domain (PBD), which has been shown to specifically bind the GTP bound form of Cdc42 or Rac, with a preference for Cdc42 [, ]. The most conserved region of GBD/PBD domains is the N-terminal Cdc42/Rac interactive binding motif (CRIB), which consists of about 16 amino acids with the consensus sequence I-S-x-P-x(2,4)-F-x-H-x(2)-H-V-G [].Although the CRIB motif is necessary for the binding to Cdc42 and Rac, it is not sufficient to give high-affinity binding [, ]. A less well conserved inhibitory switch (IS) domain responsible for maintaining the proteins in a basal (autoinhibited) state is located C-terminaly of the CRIB-motif [, , ].GBD domains can adopt related but distinct folds depending on context. Although GBD domains are largely unstructured in the free state, the IS domain forms an N-terminal β-hairpin that immediately follows the conserved CRIB motif and a central bundle of three α-helices in the autoinhibited state. The interaction between GBD domains and their respective G proteins leads to the formation of a high-affinity complex in which unstructured regions of both the effector and the G protein become rigid. CRIB motifs from various GBD domains interact with Cdc42 in a similar manner, forming an intermolecular β-sheet with strand β-2 of Cdc42. Outside the CRIB motif, the C-terminal of the various GBD domains are very divergent and show variation in their mode of binding to Cdc42, perhaps determining the specificity of the interaction. Binding of Cdc42 or Rac to the GBD domain causes a dramatic conformational change, refolding part of the IS domain and unfolding the rest [, , , , ].Some proteins known to contain a CRIB domain are listed below:Mammalian activated Cdc42-associated kinases (ACKs), nonreceptor tyrosine kinases implicated in integrin-coupled pathways.Mammalian p21-activated kinases (PAK1 to PAK4), serine/threonine kinases that modulate cytoskeletal assembly and activate MAP-kinase pathways.Mammalian Actin nucleation-promoting factor WAS (also known as Wiskott-Aldrich Symdrom Proteins, WASPs), non-kinase proteins involved in the organisation of the actin cytoskeleton.Yeast STE20 and CLA4, the homologues of mammalian PAKs. STE20 is involved in the mating/pheromone MAP kinase cascade.
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents P2Y3 receptor, which has only been experimentally characterised birds, but is known to be a functional nucleotide receptor [, ]. The P2Y3 is a non-mammalian receptor and is a species homologue of human P2Y6 receptor []. The P2Y3 receptor has been experimentally characterised in birds, and there is evidence it is expressed in ray-finned fish. The P2Y3 receptor is activated by uridine diphosphate (UDP), and to a lesser extent uridine triphosphate and adenosine diphosphate, and couples to phospholipase C [, , , ]. The P2Y3 receptor is expressed in brain, spinal cord, kidney and lung, and is highly abundant in the spleen but not in other peripheral tissues [, ].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents the P2Y2 receptor (previously known as nucleotide receptor P2U). It is expressed in in various epithelial cells [, , , ], aortic smooth muscle [, ]and the brain [, ]. It is activated by both adenine and uracil nucleotides and triphosphates but not diphosphates [, ]. P2Y2 receptors couple mainly to Gq/11 []. In bronchial and intestinal epithelia, receptor activation leads to stimulation of chloride secretion and inhibition of Na+ transport [, , ]. As a result, P2Y2 is a potential drug target for treating cystic fibrosis []. P2Y2 receptor agonists have been shown to enhance ciliary beat frequency and modulate mucin release in animals [, , ]. In vascular endothelial cells and vascular smooth muscle cells, the activation of P2Y2 receptors by ATP/UTP induces the tyrosine phosphorylation and activation of the ERK1 and ERK2 MAP kinases [, ]. The receptor mediates vasodilation to increase coronary blood [].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents P2Y6 receptor. The receptor displays pharmacological characteristics distinct from any other P2Y receptor subtype, having a preference for uridine nucleotides, with UDP being 100-fold more potent than UTP. It associates weakly with ADP, but it is not responsive to ATP [, , ]. P2Y6 is abundantly expressed in various tissues, including the spleen, placenta, kidney, adipose, bone, lung, heart, brain and skeletal muscle [, , , ]. In mouse bone marrow-derived mast cells and in the human cell line LAD2, P2Y6 receptors cooperate with cysteinyl leukotriene receptor 1 to promote cell survival and chemokine generation by a pathway involving reciprocal ligand-mediated cross-talk []. In human, rat and mouse, P2Y6 expression is increased by the stress associated with intestinal inflammation, leading to the release of CXC chemokine ligand 8 by an ERK1/2-dependent mechanism [].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents the P2Y12 receptor. It is primarily activated by ADP [, , ]and is coupled to Gi, inhibiting adenylate cyclase []. The P2Y12 receptor is highly expressed on the surface of blood platelets where it plays a role in amplification of platelet activation and aggregation [, ], and is thus a potential target for the treatment of thromboembolisms and other blood clotting disorders [, ]. The P2Y12 receptor is also expressed in the brain [], glial cells [, , ], brain capillary endothelial cells []and smooth muscle cells [], although the precise role of this subtype in these tissues is not known.
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents P2Y14 receptor (previously known as GPR105 or UDP-glucose receptor) []. It is activated exclusively by sugar nucleotides, such as UDP-glucose, UDP-galactose, UDP-glucuronic acid and UDP-N-acetylglucosamine, but not by uracil or adenine nucleotides []. It inhibits adenylate cyclase []and stimulates phospholipase C [, ]. The P2Y14 receptor is widely distributed in the human body, with moderate to high levels observed in placenta, adipose tissue, stomach, intestine, spleen, lung, heart, bone marrow, thymus, and selected brain regions [, , ].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- andtriphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents P2Y13 receptor (previously known as SP174 and GPR86), it is primarily coupled to Gi/o proteins [, ]. ADP is the naturally agonist of the P2Y13 receptor []and upon activation and coupling inhibits adenylate cyclase formation []. The P2Y12 receptor is expressed at highest levels in the brain and a number of immune tissues, particularly the spleen and is also found in the placenta, liver, bone marrow, lung [, , , ]. It is thought to play a role in hematopoiesis and the immune system [].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents the P2Y8 receptor. It was originally identified in Xenopus and found to be activated equipotently by all naturally occurring nucleoside triphosphates (ATP, CTP, GTP, ITP and UTP) but not by inorganic polyphosphates []. The receptor has been identified in human undifferentiated HL60 cells [, ]. It is currently regarded as an orphan receptor by the International Union of Basic and Clinical Pharmacology (IUPHAR). It has been suggested that this receptor may have a role in early development of the nervous system [, ].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents a predicted P2Y10 receptor. It is currently regarded as an orphan receptor by the International Union of Basic and Clinical Pharmacology (IUPHAR), because it has no known endogenous agonists. The P2Y10 receptor is nearly undetectable in undifferentiated HL60 cells, but has been found to be weakly expressed in blood leukocytes []and is expressed on adherent macrophages []. In mouse tissues, it has been demonstrated that the P2Y10 is expressed in uterus, prostate, brain, lung and skeletal muscle, but not in testis, liver, or kidney [].
There are three distinct families of extracellular receptors for purine and pyrimidine nucleotides [], known as P1, P2X and P2Y purinoceptors []. These receptors induce a wide variety of biological effects and are involved in many different cellular functions [, , ]. P2X receptors are ligand-gated ion channels, whereas P1 and P2Y receptors are rhodopsin-like G protein-coupled receptors [, ]. The families also differ by their method of activation: P1 receptors are preferentially activated by adenosine [], P2X via ATP [], whereas the P2Y receptors, in addition to being activated by ATP, are activated by different adenine and/or uridine nucleoside di- and triphosphates (ADP, UDP, UTP, UDP and UDP-glucose) [].The P2Y purinoceptors currently consist of eleven subtypes: P2Y1, P2Y2, P2Y3 P2Y4, P2Y6, P2Y8, P2Y10, P2Y11, P2Y12, P2Y13 and P2Y14 [, , ]. P2Y3 has, as yet, only been found in birds [], whilst the rest have been cloned in humans. The gaps in P2Y receptor numbering are due to the reclassification of some receptors that were initially associated with to the P2Y family. These include P2Y5 (now known as lysophosphatidic acid receptor 6), P2Y7 (now leukotriene B4 receptor) and P2Y9 (lysophosphatidic acid receptor 4) [, , , ]. P2Y purinoceptor subtypes have different pharmacological selectivities, which overlap in some cases, for various adenosine and uridine nucleotides. They are widely expressed and are involved in platelet aggregation, vasodilation and neuromodulation, and a range of other processes, such as ion flux, differentiation, and synaptic communication [, , , ]. They exert their varied biological functions based on different G-protein coupling []. Each receptor subtype can couple to multiple G proteins, either Gi, Gq/11 or Gs, triggering the activation of diverse intracellular signalling cascades (stimulation of phospholipase C through Gq/11, stimulation of adenylyl cyclase via Gs, or ihibition of adenylyl cyclase via Gi [, ]).This entry represents the P2Y11 receptor, which is the only P2Y receptor that is selective for ATP. It is not activated by UTP or UDP []. It couples to both Gs and Gq/11 and activates the phospholipase C []and adenylate cyclase [, ]signalling cascades. The receptor is found in placenta [], blood leukocytes, and in granulocytes during cell differentiation []. it is also expressed on adherent macrophages []. The receptor has been shown to be a regulator of immune response and may be a potential drug target candidate for treatment of myocardial infarction [].
This entry represents the CRIB domain superfamily. Many putative downstream effectors of the small GTPases Cdc42 and Rac contain a GTPase binding domain (GBD), also called p21 binding domain (PBD), which has been shown to specifically bind the GTP bound form of Cdc42 or Rac, with a preference for Cdc42 [, ]. The most conserved region of GBD/PBD domains is the N-terminal Cdc42/Rac interactive binding motif (CRIB), which consists of about 16 amino acids with the consensus sequence I-S-x-P-x(2,4)-F-x-H-x(2)-H-V-G [].Although the CRIB motif is necessary for the binding to Cdc42 and Rac, it is not sufficient to give high-affinity binding [, ]. A less well conserved inhibitory switch (IS) domain responsible for maintaining the proteins in a basal (autoinhibited) state is located C-terminaly of the CRIB-motif [, , ].GBD domains can adopt related but distinct folds depending on context. Although GBD domains are largely unstructured in the free state, the IS domain forms an N-terminal beta; hairpin that immediately follows the conserved CRIB motif and a central bundle of three alpha; helices in the autoinhibited state. The interaction between GBD domains and their respective G proteins leads to the formation of a high-affinity complex in which unstructured regions of both the effector and the G protein become rigid. CRIB motifs from various GBD domains interact with Cdc42 in a similar manner, forming an intermolecular beta;-sheet with strand beta;-2 of Cdc42. Outside the CRIB motif, the C-termini of the various GBD domains are very divergent and show variation in their mode of binding to Cdc42, perhaps determining the specificity of the interaction. Binding of Cdc42 or Rac to the GBD domain causes a dramatic conformational change, refolding part of the IS domain and unfolding the rest [, , , , ].Some proteins known to contain a CRIB domain are listed below:Mammalian activated Cdc42-associated kinases (ACKs), nonreceptor tyrosine kinases implicated in integrin-coupled pathways.Mammalian p21-activated kinases (PAK1 to PAK4), serine/threonine kinases that modulate cytoskeletal assembly and activate MAP-kinase pathways.Mammalian Actin nucleation-promoting factor WAS proteins (WASPs), non-kinase proteins involved in the organisation of the actin cytoskeleton.Yeast STE20 and CLA4, the homologues of mammalian PAKs. STE20 is involved in the mating/pheromone MAP kinase cascade.
Notch cell surface receptors are large, single-pass type-1 transmembrane proteins found in a diverse range of metazoan species, from human to Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses only one Notch protein, whereas in C.elegans, two receptors have been found; by contrast, four Notch paralogues (designated N1-4) have been identified in mammals, playing both unique and redundant roles. The hetero-oligomer Notch comprises a large extracellular domain (ECD), containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which are involved in ligand interactions; a negative regulatory region, including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-membrane domain (TM); a small intracellular domain (ICD), which includes a RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are involved in protein-protein interactions; and a PEST domain. Drosophila Notch also contains an OPA domain []. Notch signalling is an evolutionarily conserved pathway involved in a wide variety of developmental processes, including adult homeostasis and stem cell maintenance, cell proliferation and apoptosis []. Notch is activated by a range of ligands -the so-called DSL ligands (Delta/Seratte/LAG-2). Activation is also mediated by a sequence of proteolytic events: ligand binding leads to cleavage of Notch by ADAM proteases []at site 2 (S2) and presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) [].The last cleavage releases the Notch intracellular part of the protein (NICD) from the membrane and, upon release, the NICD translocates to the nucleus where it associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins. The subsequent recruitment of a co-activator mastermind like (MAML1) protein []promotes transcriptional activation of Notch target genes: well established Notch targets are the Hes and Hey gene families. Aberrant Notch function and signalling has been associated with a number of human disorders, including Allagile syndrome, spondylocostal dysostosis, aortic valve disease, CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), and T-cell Acute Lympho-blastic Leukemia (T-ALL); it has also been implicated in various human carcinomas [, ]. Notch3 displays a more restrictive distribution than the rest of the Notch subtypes, being expressed predominantly in vascular smooth muscle cells, the central nervous system, certain thymocytes subsets, and in regulatory T cells [].
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [, ]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble []. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. Utp13 is a nucleolar protein and component of the small subunit (SSU) processome containing the U3 snoRNA that is involved in processing of pre-18S rRNA []. Upt13 is also a component of the Pwp2 complex that forms part of a stable particle subunit independent of the U3 small nucleolar ribonucleoprotein that is essential for the initial assembly steps of the 90S pre-ribosome []. Components of the Pwp2 complex are:Utp1 (Pwp2), Utp6, Utp12 (Dip2), Utp13, Utp18, and Utp21. The relationship between the Pwp2 complex and the t-Utps complex []that also associates with the 5' end of nascent pre-18S rRNA is unclear. This is the C-terminal helical domain of yeast Utp13 and its orthologue from human, Transducin beta-like protein 3, whose function is not clear. This domain is also found in protein TORMOZ EMBRYO DEFECTIVE from plants, which is an essential protein involved in the regulation of cell division planes during embryogenesis and defines cell patterning [].
Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites [, ]. About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to - the small (S1 to S31) and the large (L1 to L44). Usually they decorate therRNA cores of the subunits. Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome [, ].The genomic structure and sequence of the human ribosomal protein L7a has been determined []. The gene contains 8 exons and 7 introns, encompassing 3179 bp. The human gene resembles other mammalian ribosomal protein genes in so far as it contains a short first exon, a short 5' untranslated leader and its transcriptional start sites at C residues embedded in a poly-pyrimidine tract [].The sequence of a gene for ribosomal protein L4 of Saccharomyces cerevisiae (Baker's yeast) has also been determined, which, unlike most of its other ribosomal protein genes, has no intron []. The single open reading frame is highly similar to mammalian ribosomal protein L7a.There appear to be two genes for L4, both ofwhich are active []. Yeast cells containing a disruption of the L4-1 gene form smaller colonies than either wild-type or disrupted L4-2 strains. Disruption of both L4 genes is lethal, probably resulting from an inability of the organism to produce functional ribosomes [].Several other ribosomal proteins have been found to share sequence similarity with L7a, including yeast NHP2 [], Bacillus subtilis hypothetical protein ylxQ, Haloarcula marismortui (Halobacterium marismortui) Hs6, and Methanocaldococcus jannaschii MJ1203.This InterPro entry focus on regions that characterise the ribosomal L7A proteins but distinguish them from the rest of the HMG-like family.
This entry represents the predicted archaeal type glutamate synthase large subunit, which includes stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit. All members in this entry contain the FMN-binding domain and some have 1-3 copies of 4Fe-4S binding domain in the N-terminal region but they lack the linker domain, found in the bacterial glutamate synthase large subunit [, ].The large (alpha, GltB) subunit of bacterial glutamate synthase (GOGAT) consists of three domains. represents a stand-alone version of the central domain, and this subgoup contains proteins that are predicted to function as part of GOGAT. This stand-alone form occurs in the archaeal type of GOGAT, where the large subunit is represented by three separate proteins, corresponding to the three domains of the "standard"bacterial enzyme []. Similar organization of GOGAT with stand-alone domains has been found in some bacteria (e.g., Sinorhizobium meliloti, Thermotoga maritima), but its function is not clear in those organisms where the "standard"bacterial form is also present (e.g., Sinorhizobium meliloti).The second (central) domain of the bacterial GOGAT large subunit consists of a linker domain and the FMN-binding domain (). The FMN-binding domain has a beta/alpha barrel topology. In this domain, the 2-iminoglutarate intermediate, formed upon the addition of ammonia onto 2-oxoglutarate, is reduced by the FMN cofactor producing the second molecule of L-glutamate []. This domain also contains the enzyme 3Fe-4S cluster [].Originally, only the ORF encoding the central domain of GOGAT was recognised and annotated as GltB in archaea, and the rest of the large subunit was thought to be missing, which may lead to some misannotations []. This led to speculations that the archaeal form of the GOGAT large subunit is the ancestral minimum form of the enzyme. Later analysis showed, however, that in all archaea where the large subunit has been found, its entire sequence is represented by three separate ORFs [].Glutamate synthase (GOGAT, GltS) is a complex iron-sulphur flavoprotein that catalyses the reductive synthesis of L-glutamate from 2-oxoglutarate (2-OG) and L-glutamine via intramolecular channeling of ammonia, a reaction in the bacterial, yeast and plant pathways for ammonia assimilation []. GOGAT is a multifunctional enzyme that functions through three distinct active centres carrying out multiple reaction steps: L-glutamine hydrolysis, conversion of 2-oxoglutarate into L-glutamate, and electron uptake from an electron donor [].There are four classes of GOGAT [, ]: 1. Bacterial NADPH-dependent GOGAT (NADPH-GOGAT, ). This standard bacterial NADPH-GOGAT is composed of a large (alpha, GltB) subunit and a small (beta, GltD) subunit.2. Ferredoxin-dependent form in cyanobacteria and plants (Fd-GOGAT from photosynthetic cells, ) displays a single-subunit structure corresponding to the large bacterial subunit.3. Pyridine-linked form in both photosynthetic and nonphotosynthetic eukaryotes (eukaryotic GOGAT or NADH-GOGAT, ) displays a single-subunit structure corresponding to the fusion of the small and the large bacterial subunits ().4. The archaeal type with stand-alone proteins corresponding to the N-terminal, FMN-binding, and the C-terminal domains of the large subunit [, ](, , ), and to the small subunit.
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions []. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [, ].Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms [, ]. Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation [], and CheA, which plays a central role in the chemotaxis system []. Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water []. The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily. HKs can be roughly divided into two classes: orthodox and hybrid kinases [, ]. Most orthodox HKs, typified by the Escherichia coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK []. Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.The response regulators for CheA bind to the P2 domain, which is found between and as either one or two copies. Highly flexible linkers connect P2 to the rest of CheA and impart remarkable mobility to the P2 domain. This feature is thought to enhance the inter CheA dimer phosphotransfer reactions within the signalling complex, thereby amplifying the phosphorylation signal [].
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions []. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [, ].Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms [, ]. Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation [], and CheA, which plays a central role in the chemotaxis system []. Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water []. The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily. HKs can be roughly divided into two classes: orthodox and hybrid kinases [, ]. Most orthodox HKs, typified by the Escherichia coli EnvZ protein, function as periplasmic membrane receptors and have a signal peptide and transmembrane segment(s) that separate the protein into a periplasmic N-terminal sensing domain and a highly conserved cytoplasmic C-terminal kinase core. Members of this family, however, have an integral membrane sensor domain. Not all orthodox kinases are membrane bound, e.g., the nitrogen regulatory kinase NtrB (GlnL) is a soluble cytoplasmic HK []. Hybrid kinases contain multiple phosphodonor and phosphoacceptor sites and use multi-step phospho-relay schemes instead of promoting a single phosphoryl transfer. In addition to the sensor domain and kinase core, they contain a CheY-like receiver domain and a His-containing phosphotransfer (HPt) domain.The response regulators for CheA bind to the P2 domain, which is found between and as either one or two copies. Highly flexible linkers connect P2 to the rest of CheA and impart remarkable mobility to the P2 domain. This feature is thought to enhance the inter CheA dimer phosphotransfer reactions within the signalling complex, thereby amplifying the phosphorylation signal [].
Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions []. Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk []. These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more []. Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) []. The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response [, ].This entry represents response regulators (RRs) with a CheY-like receiver domain fused to an RNA-binding C-terminal ANTAR domain (AmiR-like) that affects antitermination.Expression of the aliphatic amidase operon in Pseudomonas aeruginosa is controlled by an antitermination mechanism involving the AmiR/AmiC system. In the presence of small-molecule inducers, such as acetamide, premature termination is prevented by AmiR, which interacts with the nascent mRNA upstream of the terminator and probably prevents formation of the stem-loop. In the absence of inducers, the antitermination activity of AmiR is inhibited by interaction with AmiC [].Response regulators of the microbial two-component signal transduction systems typically consist of an N-terminal CheY-like receiver (phosphoacceptor) domain and a C-terminal output (usually DNA-binding) domain. In response to an environmental stimulus, a phosphoryl group is transferred from the His residue of sensor histidine kinase to an Asp residue in the CheY-like receiver domain of the cognate response regulator [, , ]. Phosphorylation of the receiver domain induces conformational changes that activate an associated output domain, which in turn triggers the response. Phosphorylation-induced conformational changes in response regulator molecule have been demonstrated in direct structural studies [].AmiR differs from the rest of the members of this group in that none of the residues involved in regulation by phosphorylation are conserved, despite the high structural homology of its N terminus to the CheY-like receiver domains. This suggests that phosphorylation plays no role in its regulation. Indeed, it has been shown that, unlike classical RRs, it is instead controlled via ligand-regulated sequestration by AmiC [, ].The C-terminal output domain of the members of this group is the RNA-binding antiterminator domain ANTAR () [, , ]. Superficially, the coiled-coil and three-helix bundle that form this domain in AmiR []appear radically different from the compact HTH DNA-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 antitermination 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 [].
