The staphostatin A polypeptide chain folds into a slightly deformed, eight-stranded β-barrel, with strands beta-4 through beta-8 forming an antiparallel sheet while the N terminus forms a ψ-loop motif. Members of this family constitute a class of cysteine protease inhibitors distinct in the fold and the mechanism of action from any known inhibitors of these enzymes [].
Class A sortases are membrane-bound cysteine transpeptidases distributed in Gram-positive bacteria (mainly present in Firmicutes). They perform a housekeeping role in the cell as members of this group are capable of anchoring a large number of functionally distinct surface proteins containing a cell wall sorting signal to an amino group located on the bacterial cell wall. They do so by catalyzing a transpeptidation reaction in which the surface protein substrate is cleaved at a conserved cell wall-sorting signal (Class A sortases recognize a canonical LPXTG motif, X can be any amino acid), and covalently linked to peptidoglycan for display on the bacterial surface. The prototypical sortase A protein from Staphylococcus aureus (named Sa-SrtA) cleaves the amide bond between threonine and glycine residues of the canonical LPXTG motif in a wide range of protein substrates with diverse functions that can promote bacterial adhesion, nutrient acquisition, host cell invasion, and immune evasion. Next, it catalyzes a transpeptidation reaction by which the proteins are covalently linked to the peptidoglycan precursor lipid II. SrtA is therefore affects the ability of a pathogen to establish successful infection. SrtA contains an N-terminal hydrophobic segment, a linker region and an extra-cellular C-terminal catalytic domain. The hydrophobic segment functions as both a signal peptide for secretion and a stop-transfer signal for membrane anchoring. The catalytic domain contains the catalytic TLXTC signature sequence where X is usually a valine, isoleucine or a threonine. The gene encoding SrtA is generally not located in the same gene cluster as its substrates while the gene encoding SrtB is usually clustered in the same locus as its substrate [, , ].
Members of this protein family are found, so far, exclusively in the genus Acinetobacter. Members average just over 600 amino acids in length, including a 22-amino acid C-terminal putative protein sorting recognition sequence, GlyGly-CTERM. The GlyGly-CTERM signal always co-occurs with a subfamily of the rhomboid family intramembrane serine proteases called rhombosortase. Members occur paired with a second rhombosortase target, with which it also shares an N-terminal motif CSLREA. This protein is designated Acinetobacter rhombotarget A (rbtA).
Aminopeptidase A (or glutamyl aminopeptidase, (); MEROPS identifier M01.003) is an aminopeptidase that releases Glu and Asp residues from the N-termini of proteins and peptides []. Although broadly distributed, the enzyme is particularly abundant in the brush borders of intestinal enterocytes and kidney []. The enzyme is activated by calcium and inhibited by metal chelators [, ]. Aminopeptidase A converts angiotensin II to angiotensin III, but in vivo conversion has only been shown in thebrain []. However, angiotensin III is a major effector peptide in control of vasopressin release and therefore control of blood pressure []. This has led to the development of therapeutic agents for the control of hypertension, such as the orally administered RB150, which is an aminopeptidase A inhibitor []. Aminopeptidase A is also abundantly expressed in the placenta and may have a role in preventing angiotensin II passing between mother and foetus []. In the kidney, monoclonal antibodies to aminopeptidase A induce albuminuria [].
This family is an archaeal variant of the (normally bacterial) putative protein-sorting integral membrane protein exosortase, hence archaeosortase. The PGF-CTERM/archaeosortase A system is related to S-layer (surface layer) production []. Moreover, it has been shown that archaeosortase A (ArtA) is involved in carboxy-terminal post-translational processing of the S-layer glycoprotein []. Archaeosortase, similarly to sortase, mediate proteolysis-coupled, covalent cell surface attachment [].
This family represents a family of bacterial phosphatidylglycerophosphatases (), known as PgpA. It appears that bacteria possess several phosphatidylglycerophosphatases, and thus, PgpA is not essential in Escherichia coli [].
Vertebrate endogenous opioid neuropeptides are released by post-translational proteolytic cleavage of precursor proteins. The precursors consist of the following components: a signal sequence that precedes a conserved region of about 50 residues; a variable-length region; and the sequence of theneuropeptide itself. Three types of precursor are known: preproenkephalin A (gene PENK), which is processed to produce 6 copies of Met-enkephalin, plus Leu-enkephalin; preproenkephalin B (gene PDYN), which is processed toproduce neoendorphin, dynorphin, leumorphin, rimorphin and Leu-enkephalin; and prepronocipeptin (gene PNOC), whose processing produces nociceptin(orphanin FQ) and two other potential neuropeptides.Sequence analysis reveals that the conserved N-terminal region of theprecursors contains 6 cysteines, which are probably involved in disulphidebond formation. It is speculated that this region might be important for neuropeptide processing [].The primary structure of rat preproenkephalin is highly similar to those of bovine and human preproenkephalins, and contains four copies of Met-enkephalin, one of Leu-enkephalin, one of Met-enkephalin-Arg6-Gly7-Leu8, and one of Met-enkephalin-Arg6-Phe7 [, ].
Thirty-eight genes that encode bombyxin, an insulin-related brain secretory peptide of the silkmoth Bombyx mori, have been characterised. These genes have been classified into four families, A, B, C and D, according to their sequence similarity [].This entry represents the bombyxin A subfamnily, and includes bombyxin A1-A9.
Tachystatin A contains a cysteine-stabilised triple-stranded β-sheet and shows features common to membrane-interactive peptides. Tachystatin A is thought to have an antimicrobial activity similar to defensins.Tachystatin A is also a chitin-binding peptide [].
Peridinin-chlorophyll-protein, a water-soluble light-harvesting complex that has a blue-green absorbing carotenoid as its main pigment, is present in most photosynthetic dinoflagellates. These proteins are composed of two similar repeated domains. These domains constitute a scaffold with pseudo-twofold symmetry surrounding a hydrophobic cavity filled by two lipid, eight peridinin, and two chlorophyll a molecules []. They have a multihelical fold which forms a boat-shaped protein shell around cofactors.
This entry represents the extracellular N-terminal domain of the cholecystokinin A receptor. This domain adopts a tertiary structure consisting of a few helical turns and a disulphide-cross linked loop. It is required for interaction of the cholecystokinin A receptor with its corresponding hormonal ligand [].
Peridinin-chlorophyll-protein, a water-soluble light-harvesting complex that has a blue-green absorbing carotenoid as its main pigment, is present in most photosynthetic dinoflagellates. These proteins are composed of two similar repeated domains. These domains constitute a scaffold with pseudo-twofold symmetry surrounding a hydrophobic cavity filled by two lipid, eight peridinin, and two chlorophyll a molecules [].
Peptide-N4-(N-acetyl-beta-glucosaminyl)asparagine amidase A (PNGase A), unlike many other amidases, is capable of hydrolysing glycopeptides with an alpha-1,3-fucosylated asparagine-bound N-acetylglucosamine (GlcNAc). PNGase A is a heterodimer composed of a large and small subunit []. This entry represents the PNGase A precursor, which contains both subunits and is activated by proteolytic cleavage.
Acyl-coenzyme A oxidase consists of three domains. An N-terminal α-helical domain, a beta sheet domain and a C-terminal catalytic domain . This entry represents the N-terminal α-helical domain [].
This domain is found at the N terminus of a group of Chlamydial lipid A biosynthesis proteins. It is also found by itself in a family of proteins of unknown function.
This entry includes bacteriocins such as Subtilosin A and Mejucin from Bacillus subtilis. Subtilosin A has a cyclized peptide backbone and forms three cross-liks between the sulphurs of Cys13, Cys7 and Cys4 and the alpha-positions of Phe22,Thr28 and Phe31 [].
Myb-related protein A (also known as A-Myb or MYBL1) is a transcription factor that binds DNA and recognises recognise the sequence 5'-YAAC[GT]G-3' [, ]. It is a component of the DREAM (MuvB/DRM) complex, which represses cell cycle-dependent genes in quiescent cells and plays a role in the cell cycle-dependent activation of G2/M genes [, ].
Bacteriochlorophyll A (or FMO) protein is involved in the energy transfer system of photosynthetic bacteria, such as Green Sulphur Bacteria. Bacteriochlorophyll A acts as a light-harvesting complex that directs light energy from the chlorosomes attached to the cell membrane to the reaction centre []. The protein forms a homotrimer, with each monomer unit containing seven molecules of bacteriochlorophyll A.
Bacteriochlorophyll A (or FMO) protein is involved in the energy transfer system of photosynthetic bacteria, such as Green Sulphur Bacteria. Bacteriochlorophyll A acts as a light-harvesting complex that directs light energy from the chlorosomes attached to the cell membrane to the reaction centre []. The protein forms a homotrimer, with each monomer unit containing seven molecules of bacteriochlorophyll A.
Acyl-coenzyme A thioesterases hydrolyse acyl-CoA to generate free fatty acid and coenzyme A. Acyl-coenzyme A thioesterase 13 (ACOT13) acts on medium (C12) and long-chain (C18) fatty acyl-CoA substrates. Naturally, it exists as a homotetramer and adopts a hotdog fold []. Homologues are found in eukaryotes and bacteria.
CarBa is the A subunit of 2-aminobiphenyl-2,3-diol 1,2-dioxygenase, which catalyzes the oxidization and subsequent ring-opening of 2-aminophenyl-2,3-diol. It is a key enzyme in the carbazole degradation pathway isolated from bacterial strains with carbazole degradation ability. The enzyme is a heterotetramer composed of two A and two B subunits. CarB belongs to the class III extradiol dioxygenase family, composed of enzymes which use a non-heme Fe(II) to cleave aromatic rings between a hydroxylated carbon and an adjacent non-hydroxylated carbon. Although the enzyme was originally isolated as a meta-cleavage enzyme for 2'-aminobiphenyl-2,3-diol involved in carbazole degradation, the enzyme has also shown high specificity for 2,3-dihydroxybiphenyl [].
This entry represents CbsA, a novel, highly glycosylated, mono-haem cytochrome b558/566 found in Sulfolobus acidocaldarius and several other members of the Sulfolobales, a branch of the Crenarchaeota [, ]. Encoded at the same locus as CbsA are: CbsB, a hydrophobic protein, SoxL, a Rieske iron-sulphur protein, SoxN, a predicted membrane-bound b-type cytochrome b, and OdsN, a protein of unknown function. Transcriptional studies suggest that these proteins may form a complex analogous to the cytochrome bc1 complex. The redox-active subunits of this complex would consist of CbsA, SoxL and SoxN, while CbsB and OdsN would be additional non-redox-active subunits.
Nucleoside diphosphate-linked moiety X motif 19 (NUDT19 or RP2p) is a coenzyme A diphosphatase. It hydrolases CoA esters, including choloyl-CoA and branched-chain fatty-acyl-CoA esters. Medium and long-chain fatty-acyl-CoA esters are the primary substrates. The protein contains a nudix hydrolase domain, a CoA-binding domain and a peroxisomal targeting signal at the C terminus, and activity in the mouse kidney is restricted to peroxisomes. The enzyme is active at pH 9 or above and requires Mn2+or Mg2+ions [].There are numerous uncharacterized bacterial and archaeal homologues.
Coenzyme A disulphide reductase () has been characterised in Staphylococcus aureus, Pyrococcus horikoshii, and Borrelia burgdorferi (Lyme disease spirochete), and inferred in several other species on the basis of high levels of CoA and an absence of glutathione as a protective thiol. Coenzyme A disulphide reductase specifically catalyses the NAD(P)H-dependent reduction of coenzyme A disulphide using FAD and NAD(P)H [, , ]. In some species the enzymes show a distinct preference for NADH or NADPH, while others can use either substrate equally well. The reduction of disulphides occurs by a thiol-disulphide exchange reaction, but involves only a single catalytic cysteine residue that forms a stable mixed disulphide with CoA during catalysis. This enzyme contains 2 FAD binding domains and a single NAD(P)H binding domain [].
This entry represents lipid A 1-diphosphate synthase LpxT (also known as YeiU) from Enterobacteriaceae. It is involved in the modification of the lipid A domain of lipopolysaccharide (LPS), which is part of Gram-negative bacteria outer membrane. Variation of the lipid A domain of LPS serves to promote bacterial resistance []. LpxT transfers a phosphate group from undecaprenyl pyrophosphate (C55-PP) to lipid A to form lipid A 1-diphosphate and contributes to the recycling of undecaprenyl phosphate (C55-P) []. It also has low undecaprenyl-diphosphate phosphatase activity in vitro[].
Acetyl-coenzyme A transporter 1 (also known as acatn) is a multipass transmembrane protein that appears to promote 9-O-acetylation in gangliosides [, ]. This entry represents acatn and its homologues.
This entry contains proteins with a winged helix DNA-binding domain, including replication factor A protein 2 (RFA2) and CST complex subunit STN1.Rfa2 (also known as RPA32) is a component of the replication protein A (RPA) complex, which binds to and removes secondary structure from ssDNA. The RPA complex is involved in DNA replication, repair, and recombination []. Stn1 is a component of the CST complex, a complex that binds to single-stranded DNA and is required to protect telomeres from DNA degradation. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. In addition to telomere protection, the CST complex has probably a more general role in DNA metabolism at non-telomeric sites [, ].
This entry consists of several bacteria specific low temperature requirement A (LtrA) protein sequences which have been found to be essential for growth at low temperatures in Listeria monocytogenes []. It also contains a number of uncharacterised fungal proteins.
The albumin I protein, a hormone-like peptide, stimulates kinase activity upon binding a membrane bound 43kDa receptor []. It is cleaved into two chains; this domain represents the "a"chain.
Some mammals, including rodents and pig, have two mannose-binding proteins, mannose-binding proteins A (MBP-A) and C. This entry represents mannose-binding protein A.MBP-A is a calcium-dependent lectin, involved in innate immune response through binding lipopolysaccharide and glycolipids containing N-acetylglucosamine [].
Escherichia coli heat-labile enterotoxin is a bacterial protein toxin with an AB5 multimer structure, in which the B pentamer () has a membrane-binding function and the A chain is needed for enzymatic activity []. The B subunits are arranged as a donut-shaped pentamer, each subunit participating in ~30 hydrogen bonds and 6 salt bridges with its two neighbours [].The A subunit has a less well-defined secondary structure. It predominantly interacts with the pentamer via the C-terminal A2 fragment, which runs through the charged central pore of the B subunits. A putative catalytic residue in the A1 fragment (Glu112) lies close to a hydrophobic region, which packs two loops together. It is thought that this region might be important for catalysis and membrane translocation [].
This entry describes A subunit of benzoyl-CoA reductase, a 4-subunit enzyme []. Many aromatic compounds are metabolized by way of benzoyl-CoA. This family shows strong sequence similarity to the 2-hydroxyglutaryl-CoA dehydratase alpha chain.
Replication gene A proteins (also known as GpA) are found in bacteriophages and in bacteria as part of a suspected prophage. These proteins function as endonucleases during DNA replication [, , ].
In molecular biology, the carboxypeptidase A inhibitor family is a family of proteins which is represented by the well-characterised metallocarboxypeptidase A inhibitor (MCPI) from potatoes, which belongs to the MEROPS inhibitor family I37, clan IE. It inhibits metallopeptidases belonging to MEROPS peptidase family M14, carboxypeptidase A.Proteins with this domain include metallocarboxypeptidase inhibitor (MCPI) and fruit-specific protein. MCPI may play a defensive role against insect attacks [].
A family of bacterial and eukaryotic endonucleases share the following characteristics: they act on both DNA and RNA, cleave double-stranded and single-stranded nucleic acids and require a divalent ion such as magnesium for their activity. A histidine has been shown []to be essential for the activity of the Serratia marcescens nuclease. This residue is located in a conserved region which also contains an aspartic acid residue that could be implicated in the binding of the divalent ion.
Proteins in this entry are more often encoded within mobilisation-related contexts than not. This includes a CRISPR-associated gene region in Geobacter sulfurreducens PCA, and plasmids in Agrobacterium tumefaciens and Coxiella burnetii. They are found together with mobile mystery protein B, a member of the Fic protein family (). Mobile mystery protein A is encoded by the upstream member of the gene pair and contains a helix-turn-helix domain.
This domain is found in bacterial and plant proteins to the C terminus of a Rieske 2Fe-2S domain (). One of the proteins the domain is found in is Pheophorbide a oxygenase (PaO) which seems to be a key regulator of chlorophyll catabolism. Arabidopsis PaO (AtPaO) is a Rieske-type 2Fe-2S enzyme that is identical to Arabidopsis accelerated cell death 1 and homologous to lethal leaf spot 1 (LLS1) of maize [], in which the domain described here is also found.
This entry represent the leader peptide domain, ending in a Gly-Gly cleavage motif, for a post-ribosomal natural product (PRNP) precursor. The corresponding modification enzymes include an ATP-GRASP enzyme and a SPASM-domain protein, related to the C-terminal region of numerous peptide-modification radical SAM enzymes.
Inhibins and activins are glycoproteins, secreted by the gonads, that belong to the transforming growth factor beta family []. They participate in differentiation and growth of diverse cell types. Inhibin inhibits secretion of follicle-stimulating hormone by the pituitary []. Inhibin has two isoforms, A and B, with the same alpha subunit but different beta subunits. Inhibin A is a dimer of alpha and beta A subunits, inhibin B is a dimer of alpha and beta B subunits. Activin A is a dimer of beta A subunits, activin AB is a dimer of beta A and beta B chains. Follistatin is bound to inhibin and activin and indirectly modulates the FSH release. In turn, FSH stimulates inhibin gene expression in the ovarian follicle [], probably mediated by cAMP []. The serum levels of inhibin, activin, and follistatin are elevated in pregnant women and decrease after delivery []. Genes coding for mouse activin beta C and beta E are closely linked and exhibit a liver-specific expression pattern in adult tissues.This entry represents inhibin beta A subunit.
Rare lipoprotein A (RlpA) is an outer membrane protein that localises to the septal ring and scattered foci along the lateral wall in Escherichia coli. In Pseudomonas aeruginosa, RlpA is a lytic transglycosylase with preference for naked glycan strands that is needed for efficient separation of daughter cells and maintenance of rod shape [].This entry represents a conserved region in RlpA and RlpA-like proteins.
F11R, also known as Junctional adhesion molecule A (JAM-1), belongs to the immunoglobulin superfamily. It is a cell adhesion molecule involved in platelet aggregation []and in transendothelial migration of leukocytes []. It binds PAR-3, and may recruit PAR-3 to tight junctions []. JAM-1 has also been shown to act as a receptor for Mammalian reovirus sigma-1 []and Human Rotavirus strain Wa [].
GPR56 is a a cell-surface G protein-coupled receptor (GPCR) which belongs to the adhesion G protein-coupled receptor (aGPCR) family, a large family of chimeric proteins that have both adhesion and signaling functions and play critical roles in diverse neurobiological processes including brain development, synaptogenesis, and myelination. This entry represents GPCR-Autoproteolysis-INducing (GAIN) subdomain A, including PLL-GAIN linker (F161-D175) region [].
This entry represents biliverdin reductase A enzymes (), reduces biliverdin (the product of haem oxygenases HO-1 and HO-2 activity) to the antioxidant bilirubin. It works by catalysing the reduction of the gamma-methene bridge of the open tetrapyrrole, biliverdin IX alpha, to bilirubin with the concomitant oxidation of a NADH or NADPH cofactor. This reaction is involved in the protohaem degradation pathway as part of porphyrin metabolism. Some enzymes are thought to use zinc as a cofactor. Human biliverdin reductase may also functions as a kinase and as a transcription factor in the MAPK (mitogen-activated protein kinase) signalling cascade [].
The serum amyloid A (SAA) proteins comprise a family of vertebrate amphipathic α-helical apolipoproteins that associate predominantly with high density lipoproteins (HDL) [, ]. They play a role in the mobilisation of cholesterol for tissue repair and regeneration []. The synthesis of these proteins is greatly increased (as much as a 1000 fold) in inflammation, being a major acute phase reactant together with C-reactive protein. They act as cytokine-like proteins that are involved in cell-cell communication and in inflammatory, immunologic, neoplastic and protective pathways []. Prolonged elevation of plasma SAA levels, as in chronic inflammation, results in a pathological condition, called amyloidosis, which affects the liver, kidney and spleen and which is characterised by the highly insoluble accumulation of SAA in these tissues. During chronic inflammation, SAA association with HDL can change its protein and lipid composition which abrogates the HDL anti-atherogenic properties, contributing to a pro-atherogenic state [, ].
This entry includes pollen allergen Pla a 1 protein from Platanus acerifolia (London plane tree) and its homologues, including pectinesterase inhibitor 12 from Arabidopsis [].The major Platanus acerifolia pollen allergen Pla a 1 belongs to a class of allergens related to proteinaceous invertase and pectin methylesterase inhibitors. Platanus acerifolia is an important cause of pollinosis; Pla a 1 has a prevalence of about 80% among plane tree pollen-allergic patients []. Recombinant Pla a 1 binds IgE in vitro, similar to its natural counterpart, rendering it suitable for specific diagnosis and structural studies [].Invertase inhibitors are structurally similar to those of pectin methylesterase (PMEIs), an enzyme that is involved in the control of pectin metabolism and is structurally unrelated to invertases []. All inhibitors share a size of about 18kDa, two strictly conserved disulfide bridges and only moderate sequence homology (about 20% sequence identity) [].
Some prokaryotes, such as the purple and green sulphur bacteria, gain energy from a mode of photosynthesis that does not generate oxygen, and is inhibited by its presence [, ]. These organisms do not include chlorophylls in their photosynthetic pigments, but instead use closely related molecules known as bacteriochlorophylls. Like chlorophylls, bacteriochlorophylls are tetrapyroles with a five-membered ring structure, differing in the side chains and hydration state of the ring structure. These alterations in structure determine what light wavelengths can be harvested by the organism [].Bacteriochlorophyll a is a photosynthetic pigment found in many of the purple bacteria. It is synthesised from protoporphyrin IX in a series of reactions including magnesium-chelation, methyl transfer, ring formation, vinyl-group reduction protochlorophyllide reduction, and finally phytol addition []. This entry represents 2-desacetyl-2-hydroxyethyl bacteriochlorophyllide a dehydrogenase, the enzyme catalysing the penultimate step in light-independent bacteriochlorophyll a biosynthesis [].
CoA-transferases catalyse the reversible transfer of of coenzyme A from CoA-thioesters to free acids, and can be divided into three families []. Family I includes transferases for 3-oxoacids (, ), short-chain fatty acids (, ) and glutaconate (). Most of the family I enzymes use acetyl-CoA or succinyl-CoA as CoA donors, and are composed of two separate polypeptides, subunits A and B, which generally aggregate as heterodimers or heterotetramers. The eukaryotic enzymes, however, are generally composed of a single two-domain polypetide representing a fusion of the A and B subunits. The transfer of CoA from one substrate to another occurs via a ping pong mechanism which involves the formation of thioester bond between CoA and a conserved glutamate residue at the active site of the enzyme [].This entry represents the CoA-binding A subunit of family I CoA-transferases. This domain forms a three-layer α-β-α sandwich where the central layer is an all parallel β-sheet, against which helices pack from both sides [, ]. The active site is thought to be located at the interface of the A and B subunits and formed by loops from both subunits.
This entry represents a conserved region within a number of eukaryotic dedicator of cytokinesis proteins (DOCK), which are guanine nucleotide exchange factors (GEFs) [, , ], that activate some small GTPases by exchanging bound GDP for free GTP such as Rac. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis []. These proteins have a DOCK-homology region 1 (DHR-1, also known as DOCK-type C2 domain) at the N-terminal and a DHR-2 (also known as DOCKER domain) at the C-terminal. The DOCKER domain () is a GEF catalytic domain organised into three lobes, A, B and C, with the Rho-family binding site and catalytic centre generated entirely from lobes B and C. This entry represents Lobe A, formed from an antiparallel array of α-helices that adopts a tetratricopeptide repeat-like fold, which through extensive contacts with lobe B, stabilises DHR-2 domain [, ].
The OapA domain gets its name from the Haemophilus influenzae protein OapA, which is required for the expression of colony opacity, thus opacity- associated protein A []. The OapA protein is required for efficient nasopharyngeal mucosal colonization, and its expression is associated with a distinctive transparent colony phenotype. OapA is thought to be a secreted protein, and its expression exhibits high-frequency phase variation []. The OapA protein contains a C-terminal OapA domain, which in the E. coli protein YtfB has been shown to bind to peptidoglycan []. A screen to identify factors that affect cell division in E. coli discovered that overproducing a fragment of YtfB, including its OapA domain, caused cells to grow as long filaments []. OapA domains are commonly associated with other domains that are involved in breaking peptidoglycan cross-links such as []. The OapA domain is distantly related to another peptidoglycan binding domain.
Herpesviruses have been implicated as a cause of tumours in a number of species. The common tumour condition of the fowl is caused by Meleagrid herpesvirus 1 (MeHV-1). Although infection is ubiquitous, only a proportion of fowl develop tumours, and the precise details of the process of tumour induction remains to be elucidated. Secretory glycoprotein GP57-65 precursor (glycoprotein A - GA) is thought to play an immunoevasive role in the pathogenesis of Marek's disease. It is a candidate for causing the early-stage immunosuppression that occurs after MDHV infection. The protein is predominantly secreted, but a small amount of mature GP57-65 is anchored in the plasma membrane, or held by other interactions. GA is similar to Herpesvirus glycoprotein C, and belongs to the immunoglobulin gene superfamily [, ].
Acetyl-coenzyme A carboxylase () (ACC), a member of the biotin-dependent enzyme family, catalyses the formation of malonyl-coenzyme A (CoA) and regulates fatty acid biosynthesis and oxidation. Biotin-dependent carboxylase enzymes perform a two step reaction: enzyme-bound biotin is first carboxylated by bicarbonate and ATP and the carboxyl group temporarily bound to biotin is subsequently transferred to an acceptor substrate such as acetyl-CoA. The carboxyltransferase domain performs the second part of the reaction [, ].The N- and C-terminal regions of the carboxyltransferase domain share similar polypeptide backbone folds, with a central β-β-alpha superhelix []. The CoA molecule is mostly associated with the N subdomain. In bacterial acetyl coenzyme A carboxylase the N and C subdomains are encoded by two different polypeptides.This entry represents the N-terminal subdomain and contains the bacterial ACC beta-subunit.
Acetyl-coenzyme A carboxylase () (ACC), a member of thebiotin-dependent enzyme family, catalyses the formation of malonyl-coenzyme A(CoA) and regulates fatty acid biosynthesis and oxidation. Biotin-dependentcarboxylase enzymes perform a two step reaction: enzyme-bound biotin is firstcarboxylated by bicarbonate and ATP and the carboxyl group temporarily boundto biotin is subsequently transferred to an acceptor substrate such asacetyl-CoA. The carboxyltransferase domain performs the second part of thereaction [, ].The N- and C-terminal regions of the carboxyltransferase domain share similar polypeptide backbone folds, with a central β-β-alpha superhelix []. The CoA molecule is mostly associated with the N subdomain.In bacterial acetyl coenzyme A carboxylase the N and C subdomains are encodedby two different polypeptides.The acetyl-coenzyme A carboxyltransferase domain is also found in the following enzymes:Methylcrotonyl-CoA carboxylase beta chain, mitochondrial precursor.Glutaconyl-CoA decarboxylase alpha subunit.Propionyl-CoA carboxylase beta chain (PCCase).This domain is the C subdomain and recognizes also the alpha-subunit of bacterial ACC.
This entry represents a group of bacterial proteins that include the lipid A deacylase LpxR from Salmonella typhimurium. LpxR is an outer membrane protein that catalyses the removal of the the 3'-acyloxyacyl moiety from lipid A. It requires Ca2+ for its activity. This enzyme folds into a 12-stranded antiparallel β-barrel with the N- and C- terminal ends pointing towards the periplasm and three extracellular loops consisting of α-helical regions at the opposite side of the β-barrel [].
This family consists of AmpG-like permease and acetyl-coenzyme A transporter 1 (AT-1). AT-1 is a probable acetyl-CoA transporter necessary for O-acetylation of gangliosides []. The signal transducer encoded by AmpG is essential for induction of chromosomal AmpC beta-lactamase in Escherichia coli by beta-lactam antibiotics and 'unspecific' inducers []. The AmpG protein probably acts as a permease in the beta-lactamase induction system and in peptidoglycan recycling.
Members of this protein group contain two antiparallel alpha helices that are linked by a highly structured inter-helix loop to form a helical hairpin; the structure is stabilised by numerous hydrophobic and electrostatic interactions. These sporulation inhibitors are antikinases that bind to the histidine kinase KinA phosphotransfer domain and act as a molecular barricade that inhibit productive interaction between the ATP binding site and the phosphorylatable KinA His residue. This results in the inhibition of sporulation (by preventing phosphorylation of spo0A) [].
This entry represents the member A of the E2/UBC superfamily of proteins found in several bacteria. The active site residues are very similar to the eukaryotic E2 proteins [, ]. Members of this family are usually fused to E1 and JAB domains C-terminal to the E2 domain. The protein is usually in the gene neighbourhood of a gene encoding a distinct metallobetalactamase family protein [].
Members of this protein group contain two antiparallel alpha helices that are linked by a highly structured inter-helix loop to form a helical hairpin; the structure is stabilised by numerous hydrophobic and electrostatic interactions. These sporulation inhibitors are antikinases that bind to the histidine kinase KinA phosphotransfer domain and act as a molecular barricade that inhibit productive interaction between the ATP binding site and the phosphorylatable KinA His residue. This results in the inhibition of sporulation (by preventing phosphorylation of spo0A) [].
Protein Unc-13 homologue A plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway []. It is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion, and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP) [, , ]. It is essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses []. It is also involved in secretory granule priming in insulin secretion [, ].
Members of this protein family belong to the same domain family as AMMECR1 , a mammalian protein whose deficit is involved in the association of Alport syndrome, midface hypoplasia, intellectual disability and elliptocytosis in humans []. Members of the present family occur as part of a three gene system with a homologue of the mammalian protein Memo (Mediator of ErbB2-driven cell MOtility), and an uncharacterised radical SAM enzyme [].
This domain is found in a number of bacterial chitinases and similar viral proteins. It is organised into a fibronectin III module domain-like fold, comprising only beta strands. Its function is not known, but it may be involved in interaction with the enzyme substrate, chitin [, ]. It is separated by a hinge region from the catalytic domain (); this hinge region is probably mobile, allowing the N-terminal domain to have different relative positions in solution [].
This entry represents subunit A of Shiga-like toxin also known as rRNA N-glycosidase; ), which are responsible for inactivation of the ribosome. Shiga-like toxins are produced by Shigella dysenteriae and by bacteriophage that infect Escherichia coli cells []. These toxins contain a single A subunit that has N-glycosidase activity and multiple copies of the B subunit that binds to the membrane glycolipid, globotriaosylceramide (Gb3). The A subunit is responsible for inhibiting protein synthesis through the catalytic inactivation of 60S ribosomal subunits. It catalyses the endohydrolysis of the N-glycosidic bond at one specific adenosine on the 28S rRNA.
ATP-binding cassette transporters (ABC) are multipass transmembrane proteins that use the energy of ATP hydrolysis to transport substrates across membrane bilayers. Members of ABC transporter subfamily A are full-length transporters [], which consist of a single long polypeptide chain organised into two tandemly arranged halves. Each half contains a membrane-spanning domain (MSD) followed by a cytoplasmic nucleotide binding domain (NBD) []. Several members of this group have been shown to mediate the transport of a variety of physiologic lipid compounds, such as sterols, phospholipids and bile acids [, ].ABCA7 plays a role in clearance of apoptotic cells by affecting their phagocytosis []. In the human visual cycle, ABCA4 acts as an inward-directed retinoid flipase, retinoid substrates imported by ABCA4 from the extracellular or intradiscal (rod) membrane surfaces to the cytoplasmic membrane surface are all-trans-retinaldehyde (ATR) and N-retinyl-phosphatidyl-ethanolamine (NR-PE). Once transported to the cytoplasmic surface, ATR is reduced to vitamin A by trans-retinol dehydrogenase (tRDH) and then transferred to the retinal pigment epithelium (RPE) where it is converted to 11-cis-retinal. ABCA4 may also play a role in photoresponse, removing ATR/NR-PE from the extracellular photoreceptor surfaces during bleach recovery []. It has been suggested that ABCA9 plays a role in monocyte differentiation and lipid homeostasis [].
Kdp is a high affinity ATP-driven K+ transport system in Escherichia coli. It is a membrane complex (KdpFABC) composed of four subunits, KdpA, KdpB, KdpC and KdpF, although KdpF is not present in some species []. It maintains intracellular homeostasis, cell shape and turgor under potassium-limiting conditions. KdpA is the K+-transporting subunit of this complex, while KdpB is a P-type ATPase that provides the energy for K+ transport. Both subunits are joined by KdpC, a probable catalytic chaperone and KdpF, that may stabilize the complex. KdpC and KdpF have single transmembrane helices and no known homologues outside of Kdp [, ].This family represents the KdpA subunit of KdpFABC complex.
Bacterial lipopolysachharides (LPS) are glycolipids that make up the outer monolayer of the outer membranes of most Gram-negative bacteria. Though LPS moleculesare variable, they all show the same general features: an outer polysaccharide which is attached to the lipid component, termed lipid A []. The polysaccharide component consists of a variable repeat-structure polysaccharide known as the O-antigen, and a highly conserved short core oligosaccharide which connects the O-antigen to lipid A. Lipid A is a glucosamine-based phospholipid that makes up the membrane anchor region of LPS []. The structure of lipid A is relatively invariant between species, presumably reflecting its fundamental role in membrane integrity. Recognition of lipid A by the innate immune system can lead to a response even at picomolar levels. In some genera, such as Neisseria and Haemophilus, lipooligosaccharides (LOS) are the predominant glycolipids []. These are analogous to LPS except that they lack O-antigens, with the LOS oligosaccharide structures limited to 10 saccharide units.This family consists of MsbB in Escherichia coli and closely related proteins in other species. MsbB is homologous to HtrB () and acts immediately after it in the biosynthesis of KDO-2 lipid A (also called Re LPS and Re endotoxin). These two enzymes act after creation of KDO-2 lipid IV-A by addition of the KDO sugars.
DNA carries the biological information that instructs cells how to exist in an ordered fashion. Accurate replication is thus one of the most important events in the cell life cycle. This function is mediated by DNA-directed DNA polymerases, which add nucleotide triphosphate (dNTP) residues to the 3'-end of the growing DNA chain, using a complementary DNA as template. Small RNA molecules are generally used as primers for chain elongation, although terminal proteins may also be used. DNA-dependent DNA polymerases have been grouped into families, denoted A, B and X, on the basis of sequence similarities [, ]. Members of family A, which includes bacterial and bacteriophage polymerases, share significant similarity to Escherichia coli polymerase I; hence family A is also known as the pol I family. The bacterial polymerases also contain an exonuclease activity, which is coded for in the N-terminal portion. Three motifs, A, B and C [], are seen to be conserved across all DNA polymerases, with motifs A and C also seen in RNA polymerases. They are centred on invariant residues, and their structural significance was implied from the Klenow (E. coli) structure. Motif A contains a strictly-conserved aspartate at the junction of a β-strand and an α-helix; motif B contains an α-helix with positive charges; and motif C has a doublet of negative charges, located in a β-turn-beta secondary structure [].This entry represents the DNA-polymerase A family.
Monellin is an intensely sweet-tasting protein derived from African berries. The protein has a very high specificity for the sweet receptors, making it ~100,000 times sweeter than sugar on a molar basis and several thousand times sweeter on a weight basis. Like the sweet-tasting protein thaumatin, it neither contains carbohydrates nor modified amino acids. Although there is no sequence similarity between the proteins, antibodies for thaumatin compete for monellin (and other sweet compounds, but not for chemically modified non-sweet monellin) and vice versa []. It is thought that native conformations are important for the sweet taste. Monellin is a heterodimer, comprising an A chain of 44 amino acid residues, and a B chain of 50 residues. The individual subunits are not sweet, nor do they block the sweet sensation of sucrose or monellin. However, blocking the single SH of monellin abolishes its sweetness, as does reaction of its methionyl residue with CNBr []. The cysteinyl and methionyl residues are adjacent, and it has therefore been suggested that this part of the molecule is essential for its sweetness []. The structure of monellin belongs to the alpha/beta class, a 5-stranded β-sheet sequestering a single α-helix. The A chain contributes 3 strands to the sheet.This entry represents the Monellin chain A.
Anti-sigma factor A is a transcriptional inhibitor that inhibits sigma 70-directed transcription by weakening its interaction with the core of the host's RNA polymerase. It is an all-helical protein, composed of six helical segments and intervening loops and turns, as well as a helix-turn-helix DNA binding motif, although neither free anti-sigma factor nor anti-sigma factor bound to sigma-70 has been shown to interact directly with DNA. In solution, the protein forms a symmetric dimer of small (10.59kDa) protomers, which are composed of helix and coil regions and are devoid of β-strand/sheet secondary structural elements [].
Monellin is an intensely sweet-tasting protein derived from African berries. The protein has a very high specificity for the sweet receptors, making it ~100,000 times sweeter than sugar on a molar basis and several thousand times sweeter on a weight basis. Like the sweet-tasting protein thaumatin, it neither contains carbohydrates nor modified amino acids. Although there is no sequence similarity between the proteins, antibodies for thaumatin compete for monellin (and other sweet compounds, but not for chemically modified non-sweet monellin) and vice versa []. It is thought that native conformations are important for the sweet taste. Monellin is a heterodimer, comprising an A chain of 44 amino acid residues, and a B chain of 50 residues. The individual subunits are not sweet, nor do they block the sweet sensation of sucrose or monellin. However, blocking the single SH of monellin abolishes its sweetness, as does reaction of its methionyl residue with CNBr []. The cysteinyl and methionyl residues are adjacent, and it has therefore been suggested that this part of the molecule is essential for its sweetness []. The structure of monellin belongs to the alpha/beta class, a 5-stranded β-sheet sequestering a single α-helix. The A chain contributes 3 strands to the sheet.
Prokaryotic exotoxin A catalyses the transfer of ADP ribose from nicotinamide adenine dinucleotide (NAD) to elongation factor-2 in eukaryotic cells, with subsequent inhibition of protein synthesis [].
Vitamin B12 dependent methylation of an sp3-hybridised carbon in chondrochloren B biosynthesis []. The enzymes in this family have a non-canonical SAM/[Fe4S4]binding motif.
Anti-sigma factor A is a transcriptional inhibitor that inhibits sigma 70-directed transcription by weakening its interaction with the core of the host's RNA polymerase. It is an all-helical protein, composed of six helical segments and intervening loops and turns, as well as a helix-turn-helix DNA binding motif, although neither free anti-sigma factor nor anti-sigma factor bound to sigma-70 has been shown to interact directly with DNA. In solution, the protein forms a symmetric dimer of small (10.59kDa) protomers, which are composed of helix and coil regions and are devoid of β-strand/sheet secondary structural elements [].
This entry includes p-aminobenzoyl-glutamate hydrolase subunit A (AbgA; MEROPS identifier M20.020). Together with subunit B it forms the heterodimer AbgAB, which has been shown not to be a dipeptidase, but to hydrolyse p-aminobenzoyl-glutamate (PABA-GLU) to form p-aminobenzoate (PABA) and glutamate [, ].AbgA is greatly similar to indole-3-acetyl-aspartic acid hydrolase from Enterobacter agglomerans [, ], also included in this family.
A number of protein families resemble HPr kinase (see ) but do not belong to that system. They include this family, which appears instead to be the marker for a different type of gene neighbourhood, in which one of the conserved neighbouring proteins resembles (but is distinct from) PqqD.
2-amino-3-ketobutyrate coenzyme A ligase (KBL), also called glycine C-acetyltransferase, is a pyridoxal phosphate (PLP) dependent enzyme that catalyses the cleavage of 2-amino-3-ketobutyrate to glycine and acetyl-CoA, the second step in the conversion of L-threonine to glycine in both prokaryotes and eukaryotes [, ].
This entry represents a group of acyl-CoA dehydrogenases from bacteria and plants, including acyl-coenzyme A oxidase 4 (ACX4) from Arabidopsis. ACX4 catalyses the desaturation of short-chain acyl-CoAs to 2-trans-enoyl-CoAs in plant peroxisomes [, ]. It is essential for embryo development []and is required for nuclear histone acetylation and DNA demethylation at some endogenous genomic loci [].
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 group of sequences contain a diverse range of gene families, which include metallopeptidases belonging to MEROPS peptidase family M14 (carboxypeptidase A, clan MC), subfamilies M14A and M14B.The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble [].ATP/GTP binding protein (AGTPBP-1/Nna1)-like proteins are active metallopeptidases that act on cytosolic proteins such as alpha-tubulin, to remove a C-terminal tyrosine. Mutations in AGTPBP-1/Nna1 cause Purkinje cell degeneration (pcd). AGTPBP-1/Nna1-like proteins from the different phyla are highly diverse, but they all contain a unique N-terminal conserved domain right before the CP domain. It has been suggested that this N-terminal domain might act as a folding domain [, , , ].The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ].
Members of the golgin subfamily A were identified as Golgi auto-antigens []. They might be involved in maintaining cis-Golgi structure []. One of the members of this family, member 2 or GM130, is a specific interacting partner of the small GTPase Rab1b []and plays a key role in the disassembly and reassembly of the Golgi apparatus during mitosis. GM130 is also involved in vesicle tethering and fusion at the cis-cisternae to facilitate transit between transport vesicles and the stacked cisternae. It interacts with GRASPs proteins, which mediate the stacking of Golgi cisternae []. Additionally, GM130 was localised to the spindle poles and regulates microtubule organization [].Structurally, GM130 is comprised of six coiled-coil regions in the middle, a Golgi-targeting domain at the C terminus, and a p115-interacting motif at the N terminus [].
This entry represents inducible mutagenesis protein A (ImuA), believed to be involved in DNA damage tolerance in a number of bacteria. This protein is often encoded in a operon with DnaE2 (a second copy of the catalytic subunit of DNA polymerase III), and ImuB (whose function is not known though it is similar to the Y-family of DNA polymerases), though the genes may also be encoded in separate regions. In Caulobacter crescentus (Caulobacter vibrioides) the imuAB/dnaE2 operon is induced by DNA damage in a RecA-dependent manner and is required for the error-prone processing of DNA lesions []. Strains deficient in these genes showed extreme sensitivity to mutagenic agents such as UV or the drug mitC. The function of ImuA is not known but sequence analysis suggests that it contains a P-loop nucleoside triphosphate hydrolase domain.
Equid herpesvirus 1 (Equine herpesvirus 1, EHV-1) glycoprotein 13 (EHV-1 gp13) has the characteristic features of a membrane-spanning protein: an N-terminal signal sequence; a hydrophobic membrane anchor region; a charged C-terminal cytoplasmic tail; and an exterior domain with nine potential N-glycosylation sites []. EHV-1 gp13 is the structural homologue of the gC-like glycoproteins of the Human herpesvirus 1 (HHV-1) and Human herpesvirus 2 (HHV-2) (gC-1 and gC-2 respectively), Pseudorabies virus (strain Indiana-Funkhauser/Becker) (PRV) (gIII) and Human herpesvirus 3 (HHV-3) (gp66). Secretory glycoprotein GP57-65 precursor (glycoprotein A - GA) is similar to Herpesvirus glycoprotein C, and belongs to the immunoglobulin gene superfamily [, ]. GA is thought to play an immunoevasive role in the pathogenesis of Marek's disease. It is a candidate for causing the early-stage immunosuppression that occurs after MDHV infection.
This group of peptidases, belong to MEROPS peptidase family C69 (dipeptidase, clan PB). They are mainly dipeptidases []and incude dipeptidase A from Lactobacillus helveticus (MEROPS identifier C69.001). Comparative sequence and structural analysis, particularly to penicillin V acylase (MEROPS peptidase family C59) revealed a cysteine as the catalytic nucleophile as well as other conserved residues important for catalysis []. In general, C69 family is variable in sequence and exhibits great diversity in substrate specificity, to include enzymes such as choloyglycine hydrolases, acid ceramidases, isopenicillin N acyltransferases, and a subgroup of eukaryotic proteins with unclear function.A cysteine peptidase is a proteolytic enzyme that hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. Hydrolysis involves usually a catalytic triad consisting of the thiol group of the cysteine, the imidazolium ring of a histidine, and a third residue, usually asparagine or aspartic acid, to orientate and activate the imidazolium ring. In only one family of cysteine peptidases, is the role of the general base assigned to a residue other than a histidine: in peptidases from family C89 (acid ceramidase) an arginine is the general base. Cysteine peptidases can be grouped into fourteen different clans, with members of each clan possessing a tertiary fold unique to the clan. Four clans of cysteine peptidases share structural similarities with serine and threonine peptidases and asparagine lyases. From sequence similarities, cysteine peptidases can be clustered into over 80 different families []. Clans CF, CM, CN, CO, CP and PD contain only one family.Cysteine peptidases are often active at acidic pH and are therefore confined to acidic environments, such as the animal lysosome or plant vacuole. Cysteine peptidases can be endopeptidases, aminopeptidases, carboxypeptidases, dipeptidyl-peptidases or omega-peptidases. They are inhibited by thiol chelators such as iodoacetate, iodoacetic acid, N-ethylmaleimide or p-chloromercuribenzoate.Clan CA includes proteins with a papain-like fold. There is a catalytic triad which occurs in the order: Cys/His/Asn (or Asp). A fourth residue, usually Gln, is important for stabilising the acyl intermediate that forms during catalysis, and this precedes the active site Cys. The fold consistsof two subdomains with the active site between them. One subdomain consists of a bundle of helices, with the catalytic Cys at the end of one of them, and the other subdomain is a β-barrel with the active site His and Asn (or Asp). There are over thirty families in the clan, and tertiary structures have been solved for members of most of these. Peptidases in clan CA are usually sensitive to the small molecule inhibitor E64, which is ineffective against peptidases from other clans of cysteine peptidases [].Clan CD includes proteins with a caspase-like fold. Proteins in the clan have an α/β/α sandwich structure. There is a catalytic dyad which occurs in the order His/Cys. The active site His occurs in a His-Gly motif and the active site Cys occurs in an Ala-Cys motif; both motifs are preceded by a block of hydrophobic residues []. Specificity is predominantly directed towards residues that occupy the S1 binding pocket, so that caspases cleave aspartyl bonds, legumains cleave asparaginyl bonds, and gingipains cleave lysyl or arginyl bonds.Clan CE includes proteins with an adenain-like fold. The fold consists of two subdomains with the active site between them. One domain is a bundle of helices, and the other a β-barrell. The subdomains are in the opposite order to those found in peptidases from clan CA, and this is reflected in the order of active site residues: His/Asn/Gln/Cys. This has prompted speculation that proteins in clans CA and CE are related, and that members of one clan are derived from a circular permutation of the structure of the other.Clan CL includes proteins with a sortase B-like fold. Peptidases in the clan hydrolyse and transfer bacterial cell wall peptides. The fold shows a closed β-barrel decorated with helices with the active site at one end of the barrel []. The active site consists of a His/Cys catalytic dyad.Cysteine peptidases with a chymotrypsin-like fold are included in clan PA, which also includes serine peptidases. Cysteine peptidases that are N-terminal nucleophile hydrolases are included in clan PB. Cysteine peptidases with a tertiary structure similar to that of the serine-type aspartyl dipeptidase are included in clan PC. Cysteine peptidases with an intein-like fold are included in clan PD, which also includes asparagine lyases.
This entry represents the N-acetylglucosamine-binding protein A (GbpA) of various pathogenic bacteria, including Vibrio cholerae, which is the etiologic agent of cholera in humans. GbpA binds to chitin and specifically to the chitin monomer N-acetylglucosamine (GlcNAc), a sugar residue that is also found on the surface of epithelial cells. Intestinal colonization of V. cholerae occurs in a stepwise fashion, initiating with attachment to the small intestinal epithelium []. This attachment is followed by expression of the toxin co-regulated pilus, microcolony formation, and cholera toxin production. GlcNAc binding protein A (GbpA) is a secreted attachment factor, which functions in attachment to environmental chitin sources as well as to intestinal substrates. GbpA is expressed and secreted at low-cell densities and is suppressed at high cell-densities and in particular in cells that produced HapR, the central regulator of the cell density dependent quorum sensing system of V. cholerae. HapR activates the expression of genes encoding the secreted proteases HapA and PrtV, which degrade GbpA; suggested that the fluctuation of GbpA levels is a consequence of the levels of bacterial proteases in response to quorum sensing signals. This provides a mechanism for GbpA-mediated attachment to, and detachment from, surfaces in response to environmental cues [].
Coenzyme A pyrophosphatase (CoAse), a member of the Nudix hydrolase superfamily, functions to catalyse the elimination of oxidized inactive CoA, which can inhibit CoA-utilizing enzymes. The need of CoAses mainly arises under conditions of oxidative stress. CoAse has a conserved Nudix fold and requires a single divalent cation for catalysis. In addition to a signature Nudix motif G[X5]E[X7]REUXEEXGU, where U is Ile, Leu, or Val, CoAse contains an additional motif upstream called the NuCoA motif (LLTXT(SA)X3RX3GX3FPGG) which is postulated to be involved in CoA recognition []. CoA plays a central role in lipid metabolism. It is involved in the initial steps of fatty acid synthesis in the cytosol, in the oxidation of fatty acids and the citric acid cycle in the mitochondria, and in the oxidation of long-chain fatty acids in peroxisomes. CoA has the important role of activating fatty acids for further modification into key biological signalling molecules [, ].Proteins in this family include Nudt7 and Nudt8. Nudt7 mediates the cleavage of CoA, CoA esters and oxidized CoA with similar efficiencies, yielding 3',5'-ADP and the corresponding 4'-phosphopantetheine derivative as products. Preferentially hydrolyzes medium-chain acyl-CoAs and bile acid-CoAs []. This entry also includes yeast Pcd1, which act as peroxisomal pyrophosphatase with specificity for coenzyme A and CoA derivatives [, ].
Catabolite control protein A is a LacI family global transcriptional regulator found in Gram-positive bacteria. CcpA is involved in repressing carbohydrate utilization genes [ex: alpha-amylase (amyE), acetyl-coenzyme A synthase (acsA)]and in activating genes involved in transporting excess carbon from the cell [e.g. acetate kinase (ackA), alpha-acetolactate synthase (alsS)]. Additionally, disruption of CcpA in Bacillus megaterium, Staphylococcus xylosus, Lactobacillus casei and Lactobacillus pentosus also decreases growth rate, which suggests CcpA is involved in the regulation of other metabolic pathways []. Its structure has been solved [].
MpaA is a murein-tripeptide-specific zinc carboxypeptidase that hydrolyses the gamma-D-glutamyl-diaminopimelic acid bond in the murein tripeptide (L-Ala-gamma-D-Glu-meso-Dap), derived from the turnover of murein but it is not active against the murein tetrapeptide (L-Ala-gamma-D-Glu-meso-Dap-D-Ala). MpaA is a dimeric metalloprotein, containing one zinc ion per chain. Crystal structure studies revealed that this protein has high structural similarity to eukaryotic zinc carboxypeptidases and that it has a narrower substrate specificity due to an additional structure that partially occludes the substrate-binding groove []. MpaA belongs to the peptidase M14 family.
This superfamily consists of protein sequences that are similar to the nuclease A inhibitor expressed by bacteria of the genus Anabaena (NuiA, ). This sequence is organised to form an α-β-alpha sandwich fold, which is similar to the PR-1-like fold. NuiA interacts with nuclease A by means of residues located at one end of the molecule, including residues making up the loop between helices III and IV and the loop between strands C and D. The mechanism of inhibition of nuclease A by NuiA is as yet incompletely understood [].
This family consists of protein sequences that are similar to the nuclease A inhibitor expressed by bacteria of the genus Anabaena (NuiA, ). This sequence is organised to form an α-β-alpha sandwich fold, which is similar to the PR-1-like fold. NuiA interacts with nuclease A by means of residues located at one end of the molecule, including residues making up the loop between helices III and IV and the loop between strands C and D. The mechanism of inhibition of nuclease A by NuiA is as yet incompletely understood [].
In Verrucomicrobium spinosum and Chthoniobacter flavus, a four-gene operon that includes proteins with an N-terminalsignal sequence for cleavage and methylation recurs many times. Each operon is likely to encode a membrane complex, the function of which is unknown. This entry represents a long protein from this putative membrame complex, with members averaging about 1300 amino acids. The N-terminal region includes an apparent signal sequence. The function is unknown. Most cassettes are adjacent to an unusually large protein with both an outer membrane autotransporter region and PEP-CTERM putative protein-sorting motif.
The repulsive guidance molecule (RGM) family consists of bone morphogenetic protein (BMP) coreceptors RGMA, DRAGON (RGMB), and hemojuvelin (RGMC). RGMs are a class of GPI-anchored glycoproteins that signal via the neogenin and the BMP pathways [, ].RGMA binds its receptor neogenin and is also a BMP co-receptor []. In addition to controlling axon guidance, the binding of RMGA to neogenin regulates neuronal death and cell differentiation in the developing brain [, ]and inhibits mammalian CNS neurite outgrowth after injury []. RGMA plays a role in multiple sclerosis [].
This domain may occur as essentially the full length of a protein, except for an N-terminal sequence and a C-terminal protein-sorting signal such as PEP-CTERM or LPXTG. Most often, the putative surface protein is longer, in which this domain is found N-terminal to repeating stalk domains in bacterial surface proteins. This is one of very few domains for which both anchoring domains occur, and designated choice-of-anchor A domain. The structure model of this domain is highly similar to the Ice_binding adhesive proteins (). However, some of the bacterial species in which this domain can be found, are less likely to be water-based and thus the function seems unlikely to be ice-binding. This domain is found in a Bacillus anthracis protein with the gene name BA_0871 or BASH2_04951, which was described to be collagen binding and to be involved in the bacterial pathogenicity []. BA0871, has five CNA-family protein B-type repeats toward the C terminus and an LPXTG cell wall attachment motif [].
Evasins are secreted glycoproteins from ticks, that enhance host blood flow and have anti-inflammatory activity. They bind to chemokines and prevent leukocyte recruitment [, , , ]. Based on the chemokine selectivity they can be divided in two classes: Class A binds CC chemokines and includes Evasin-1 (EVA-1) and Evasin-4, being EVA-1 more selective; Class B Evasins include Evasin-3 which binds and inhibits several CXC chemokines but not CC chemokines.This family represents class A evasins, which contain eight conserved Cys residues that define four intramolecular disulfide bonds. The N- and C-terminal regions are flexible, extend from either side of the core and form a concave surface with the first β-sheet suitable for binding another EVA-1 molecule or to a chemokine. There are two Gly residues strictly conserved. Predicted glycosylation sites were identified on the exterior surface of the structure. Due to its anti-inflammatory activity, these proteins are interesting therapeutic agents [, ].
Amidase signature (AS) enzymes are a large group of hydrolytic enzymes that contain a conserved stretch of approximately 130 amino acids known as the AS sequence. They are widespread, being found in both prokaryotes and eukaryotes. AS enzymes catalyse the hydrolysis of amide bonds (CO-NH2), although the family has diverged widely with regard to substrate specificity and function. Nonetheless, these enzymes maintain a core alpha/beta/alpha structure, where the topologies of the N- and C-terminal halves are similar. AS enzymes characteristically have a highly conserved C-terminal region rich in serine and glycine residues, but devoid of aspartic acid and histidine residues, therefore they differ from classical serine hydrolases. These enzymes posses a unique, highly conserved Ser-Ser-Lys catalytic triad used for amide hydrolysis, although the catalytic mechanism for acyl-enzyme intermediate formation can differ between enzymes [].Examples of AS enzymes include:Peptide amidase (Pam) [], which catalyses the hydrolysis of the C-terminal amide bond of peptides.Fatty acid amide hydrolases [], which hydrolyse fatty acid amid substrates (e.g. cannabinoid anandamide and sleep-inducing oleamide), thereby controlling the level and duration of signalling induced by this diverse class of lipid transmitters.Malonamidase E2 [], which catalyses the hydrolysis of malonamate into malonate and ammonia, and which is involved in the transport of fixed nitrogen from bacteroids to plant cells in symbiotic nitrogen metabolism.Subunit A of Glu-tRNA(Gln) amidotransferase [],a heterotrimeric enzyme that catalyses the formation of Gln-tRNA(Gln) by the transamidation of misacylated Glu-tRNA(Gln) via amidolysis of glutamine.In many species, Gln-tRNA ligase is missing. tRNA(Gln) is misacylated with Glu after which a heterotrimeric amidotransferase converts Glu to Gln. This group represents the amidase chain of the heterotrimer, encoded by the gatA gene called glutamyl-tRNA(Gln) amidotransferase, A subunit . This enzyme functions as an alternative to a direct Gln-tRNA synthetase (Gln-tRNA ligase) in mitochondria, chloroplasts, Gram-positive bacteria, cyanobacteria, and the Archaea. The archaea have an Asp-tRNA(Asn) amidotransferase instead of an Asp-tRNA ligase. In the archaea, a paralog of gatB is found, here designated gatB_rel, that is a candidate B subunit of the Asp-tRNA(Asn) amidotransferase. The gatA-encoded subunit may be shared by gatB and gatB_rel.
This family represents a group of fungal proteins which belongs to the Fat storage-inducing transmembrane protein family (FITM), including acyl-coenzyme A diphosphatase YFT2 from Saccharomyces cerevisiae, the yeast orthologue of human FIT2 []. This protein is required for ER membrane biosynthesis in response to ER stress, for maintaining ER structure and for lipid droplets (LDs) biogenesis []. YFT2 may support directional budding of nascent LDs from the ER into the cytosol by reducing DAG levels at sites of LD formation [, ].
This entry represents Acyl-coenzyme A diphosphatase SCS3 from fungi, a member of the fat storage-inducing transmembrane protein family (FITM) and an orthologue of human FIT2. This protein is required for maintaining ER structure and for lipid droplets (LDs) biogenesis [, , ]. SCS3 may support directional budding of nascent LDs from the ER into the cytosol by reducing DAG levels at sites of LD formation [, ]and it is involved in phospholipid biosynthesis [, , ].
Quinolinate synthetase catalyses the second step of the de novobiosynthetic pathway of pyridine nucleotide formation. In particular, quinolinate synthetase is involved in the condensation of dihydroxyacetone phosphate and iminoaspartate to form quinolinic acid []. This synthesis requires two enzymes, an FAD-containing "B protein"and an "A protein". B protein converts L-aspartate to iminoaspartate. The A protein, NadA, converts iminoaspartate to quinolate. NadA harbours a [4Fe-4S]cluster [].
Aurora kinase A (AURKA, also known as Aurora 2) is a mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression. It associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in regulating centrosome maturation and separation and bipolar spindle assembly [, ]. It also plays an important role in the spindle checkpoint regulation []. Aurora A promotes mitotic entry by controlling activation of Cyclin-B/Cdk-1. It regulates the progression of mitosis by phosphorylation of multiple substrates, such as Polo-like kinase-1, ajuba, enhancer of filamentation 1, BORA, TPX2, PLK-1, astrin, growth arrest and DNA damage-inducible 45alpha, transforming acidic coiled-coil containing protein 3 (TACC3) and centrosomin []. During mitotic exit, AURKA is targeted for degradation through its interaction with the multi-subunit E3-ubiquitin ligase anaphase promoting complex/cyclosome (APC/C) [].The Aurora kinases are highly conserved serine/threonine kinases that regulate chromosomal alignment and segregation during mitosis and meiosis. Three mammalian Aurora kinases, Aurora A, B and C, have been identified. They all contain a protein kinase domain and a destruction box (D-box) recognised by the multi-subunit E3-ubiquitin ligase anaphase promoting complex/cyclosome (APC/C), which mediates their proteasomal degradation. However, their N-terminal domain share little sequence identity and confer unique protein-protein interaction abilities among the Aurora kinases []. They are differentially expressed at high levels in rapidly dividing tissues such as hematopoietic cells (A and B) andgerm cells (C only). Their expression is low or absent in most adult tissues due to their lower rates of proliferation [].
