Members of this family resemble cytochrome P450 by homology, but lack a critical heme-binding Cys residue. Members in general are encoded next to a glycosyltransferase gene in a natural products biosynthesis cluster, physically interact with it, and help the glycosyltransferase achieve high specificity while retaining high activity. Many members of this family assist in the attachment of a sugar moiety to a natural product such as a polyketide [
]. This entry includes Streptomyces venezuelae DesVII and its homologues, such as OleP1 from the oleandomycin-producingStreptomyces antibioticus, DnrQ from the doxorubicin-producing Streptomyces peucetius, and TylMIII from the tylosin-producing Streptomyces fradiae [
]. DesVII is a glycosyltransferase involved in the biosynthesis of the macrolide antibiotics methymycin, neomethymycin, narbomycin, and pikromycin in Streptomyces venezuelae. It requires an auxiliary activator protein DesVIII for full activity. DesVII/DesVIII catalyses the attachment of TDP-desosamine to 10-deoxymethynolide or narbonolide [
].
The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids [
,
].The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
This entry represents a conserved site found in the alpha subunit which includes the conserved histidine residue.
E or "early"set domains are associated with the catalytic domain of chitobiase and beta-hexosaminidases (
) at the C terminus. Chitobiase digests the beta, 1-4 glycosidic bonds of the N-acetylglucosamine (NAG) oligomers found in chitin, an important structural element of fungal cell wall and arthropod exoskeletons. It is thought to proceed through an acid-base reaction mechanism, in which one protein carboxylate acts as the catalytic acid, while the nucleophile is the polar acetamido group of the sugar in a substrate-assisted reaction with retention of the anomeric configuration [
]. The C terminus of chitobiase is composed of a beta sandwich structure [] and may be related to the immunoglobulin and/or fibronectin type III superfamilies. E set domains are associated with different types of catalytic domains at either the N-terminal or C-terminal end and may be involved in homodimeric/tetrameric/dodecameric interactions.
PolD2 (DNA polymerase delta, subunit 2) is an auxiliary subunit of the eukaryotic DNA polymerase delta (PolD) complex thought to play a regulatory role and to serve as a scaffold for PolD assembly by interacting simultaneously with all of the other three subunits. PolD2 is catalytically inactive and lacks the active site residues required for phosphoesterase activity in other members of this superfamily. PolD2 is also involved in the recruitment of several proteins regulating DNA metabolism, including p21, PDIP1, PDIP38, PDIP46, and WRN. Human PolD consists of four subunits: p125 (PolD1), p50 (PolD2), p66(PolD3), and p12(PolD4). PolD is one of three major replicases in eukaryotes. PolD also plays an essential role in translesion DNA synthesis, homologous recombination, and DNA repair. Within the PolD complex, PolD2 tightly associates with PolD3 [
,
]. PolD2 belongs to the metallophosphatase (MPP) superfamily.
This entry represents IL27-A proteins (known as IL-30/IL27-p28). Interleukin-27 is a heterodimeric cytokine composed of two subunits; IL27-A (IL27-p28) and Epstein-Barr virus-induced gene 3 (EBI3, also known as IL-27B) [
]. IL27 is a cytokine with pro- and anti-inflammatory properties, that can regulate T-helper cell development, suppress T-cell proliferation, stimulate cytotoxic T-cell activity, induce isotype switching in B-cells, and that has diverse effects on innate immune cells [
]. Another important role of IL-27 is its antitumor activity as well as its antiangiogenic activity with activation of production of antiangiogenic chemokines such as IP-10/CXCL10 and MIG/CXCL9. In vein endothelial cells, it induces IRF1/interferon regulatory factor 1 and increase the expression of MHC class II transactivator/CIITA with resulting up-regulation of major histocompatibility complex class II. IL-27 also demonstrates antiviral activity with inhibitory properties on HIV-1 replivation [,
].
Porins are found in the outer membranes of Gram-negative bacteria,
mitochondria and chloroplasts, where they form ion-selective channels forsmall hydrophilic molecules (up to ~600 D) [
,
]. X-ray structureanalyses of several bacterial porins [
,
,
] have revealed a large 16-strandedanti-parallel β-barrel structure enclosing the transmembrane pore, by
contrast with all other integral membrane proteins described to date,which are α-helical. Three subunits form a trimer; the 3-fold axis is
approximately parallel to the barrel axes and is assumed to beperpendicular to the membrane plane.
From the range of porins now known, similarities have been observed between
porins from different species, and between porins of different specificitywithin the same species. But most porins cannot be related to each other on
the basis of sequence alone, and this is reflected in the lengths of theknown porin sequences, which range from 282-483 residues/monomer.
This entry represents a domain found in class IV SAM-dependent methyltransferases TRM10-type [
]. Methyltransferases classified as class IV (SPOUT) are homodimers and methylate only RNA. The common core of the SPOUT fold contains a five-stranded beta sheet, flanked by two layers of alpha helices. The core can be divided into two subdomains, both displaying an alpha/beta architecture: (1) the N-terminal strands exhibit a Rossmanoidal alpha/beta fold while (2) an important part of the C-terminal (~ 30 residues) is tucked back into the structure forming a conserved topological trefoil knot where SAM binding occurs. The active site, located at the interface of the two subunits, isformed by amino acids from both monomers [
,
].TRM10-type methyltransferases include tRNA (guanine(9)-N(1))-methyltransferase, tRNA (adenine(9)-N(1))-methyltransferase and RNA (guanine-9-)-methyltransferase domain-containing protein. TRM10 homologues are widely found in eukaryotes and archaea, but not in bacteria.
Angiotensin II is a blood-borne hormone produced in the circulation, it is also formed in many tissues such as the brain, kidney, heart, and blood vessels, where angiotensin II functions as a paracrine and autocrine hormone. The known actions of angiotensin II are mediated through two angiotensin receptor subtypes, Angiotensin II receptor 1 and angiotensin II receptor 2, which are members of the seven transmembrane rhodopsin-like G-protein coupled receptor family. These subtypes are important in the renin-angiotensin system, as they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II []. They also stimulate increased fluid intake and regulate the neuroendocrine system [].This entry represents the angiotensin II receptor family. It also includes the relaxin-3 receptor 2, also known as GPCR142 [
], and the apelin receptor from lower vertebrates [].
This entry includes the putative hydrocarbon oxygenase, MocD, a bacterial rhizopine (3-O-methyl-scyllo-inosamine, 3-O-MSI) oxygenase, and other related proteins. It has been proposed that MocD, MocE (Rieske-like ferredoxin), and MocF (ferredoxin reductase) under the regulation of MocR, act in concert to form a ferredoxin oxygenase system that demethylates 3-O-MSI to form scyllo-inosamine. This domain family appears to be structurally related to the membrane fatty acid desaturases and the alkane hydroxylases. They all share in common extensive hydrophobic regions that would be capable of spanning the membrane bilayer at least twice. Comparison of sequences also reveals the existence of three regions of conserved histidine cluster motifs that contain eight histidine residues: HXXXH, HXXHH, and HXXHH. These histidine residues are reported to be catalytically essential and proposed to be the ligands for the iron atoms contained within homologs, stearoyl CoA desaturase and alkane hydroxylase [
].
Domain C is the largest domain in this unusual penicillin-binding protein (PBP), Tp47. This domain is mainly characterised by an immunoglobulin fold with two opposing β-sheets that form the typical barrel-like structure. In contrast to the classical immunoglobulin fold, however, this has an additional β-strand inserted after strand 3. Also, the strands are connected by rather large loops. Helices are inserted between strands 2 and 3 and between strands 4 and 5. Domain C interacts with domain B via a surface that has a slightly concave, goblet-like shape in addition to interacting tightly with domain A and weakly with domain D. Tp47 is unusual in that it displays beta-lactamase activity, so it does not fit the classical structural and mechanistic paradigms for PBPs, and thus Tp47 appears to represent a new class of PBP [
].
This entry represents the transforming growth factor (TGF)-beta receptor type-2, which has serine/threonion kinase activity (
) and uses magnesium or manganese as a cofactor. These proteins are the receptors for TGF-beta, a large family of growth and differentiation factors that mobilise complex signalling networks to regulate cellular differentiation, proliferation, motility, adhesion, and apoptosis [
]. On ligand binding, the type-2 TGF-beta receptor forms a receptor complex consisting of two type II and two type I transmembrane serine/threonine kinases. Type-2 receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators. Defects in TGF-beta receptor type-2 are linked to several diseases, including hereditary non-polyposis colorectal cancer type 6 (HNPCC6) [
], oesophageal cancer [], Loeys-Dietz syndrome types 1B (LDS1B) and 2B (LDS2B) [], aortic aneurysm familial thoracic type 3 (AAT3), and Marfan syndrome type 2 (MFS2) [].
Lysozymes are ancient and important components of the innate immune system of animals that hydrolyse peptidoglycan, the major bacterial cell wall polymer. Various mechanisms have evolved by which bacteria can evade this bactericidal enzyme, one being the production of lysozyme inhibitors. MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli [
]. Structural analyses show that the invariant loop of MliC plays a crucial role in the inhibition of the lysozyme by its insertion into the active site cleft of the lysozyme, where the loop forms hydrogen and ionic bonds with the catalytic residues [].Interestingly, lipoprotein LprI has a C-terminal MliC domain, and has
been identified only in virulence-associated mycobacterial strains, where it acts as a lysozyme inhibitor [].
This entry reprsents ATP-dependent DNA helicase PcrA in bacteria, wich belongs to the UvrD/Rep helicase family. It has a broad nucleotide specificity, even being able to hydrolyze ethenonucleotides, and is able to couple the hydrolysis to unwinding of DNA substrates. It is a 3'-5' helicase but at high protein concentrations it can also displace a substrate with a 5' tail [
,
,
]. The action of the 3'5' bacterial DNA helicase is based upon two separate but coupled activities, ssDNA translocation and duplex
destabilisation, and is driven by energy derived from the continuous ATP-binding and hydrolysis events that take place in the active-site cleft. The resultingconformational changes that accompany these events underpin the coupling process and allow the helicase to translocate along the DNA, destabilising the duplex and
separating the two strands in an active process [].
This entry represents the RNA recognition motif 3 (RRM3) of polypyrimidine tract-binding protein 2 (PTBP2).PTBP2 is a homologue of PTB (PTBP1), a splicing repressor factor implicated in the control of alternative exon selection during mRNA processing of many different transcribed genes, including its own pre-mRNA. PTBP2 is expressed at high levels in adult brain, muscle and testis [
]. PTB and PTBP2 bind to the same RNA sequences and have similar effects on alternative splicing events. However, differential expression of PTB and PTBP2 can lead to the generation of alternatively spliced mRNAs []. During neuronal differentiation, microRNA miR-124 downregulates PTB expression, which in turn leads to upregulation of PTBP2. Later in development, the expression of PTBP2 decreases and this leads to a second wave of alternative splicing changes characteristic of adult brain and essential for brain development [].
This entry represents the RNA recognition motif 4 (RRM4) of polypyrimidine tract-binding protein 2 (PTBP2).PTBP2 is a homologue of PTB (PTBP1), a splicing repressor factor implicated in the control of alternative exon selection during mRNA processing of many different transcribed genes, including its own pre-mRNA. PTBP2 is expressed at high levels in adult brain, muscle and testis [
]. PTB and PTBP2 bind to the same RNA sequences and have similar effects on alternative splicing events. However, differential expression of PTB and PTBP2 can lead to the generation of alternatively spliced mRNAs []. During neuronal differentiation, microRNA miR-124 downregulates PTB expression, which in turn leads to upregulation of PTBP2. Later in development, the expression of PTBP2 decreases and this leads to a second wave of alternative splicing changes characteristic of adult brain and essential for brain development [].
This entry represents the RNA recognition motif (RRM) of snRNP35 (also known as U11/U12-35K), which is one of the components of the U11/U12 snRNP, a spliceosome required for splicing U12-type nuclear pre-mRNA introns [
,
]. U11/U12-35K is highly conserved among bilateria and plants, but is lacking in some organisms, such as Saccharomyces cerevisiae and Caenorhabditis elegans. Moreover, U11/U12-35K shows significant sequence similarity to U1 snRNP-specific 70kDa protein (U1-70K or snRNP70) [
]. U11/U12-35K contains a conserved RNA recognition motif (RRM), followed by an adjacent glycine-rich region, and an Arg-Asp and Arg-Glu dipeptide repeat-rich domain, making U11/U12-35K a possible functional analogue of U1-70K. It may facilitate 5' splice site recognition in the minor spliceosome and play a role in exon bridging, interacting with components of the major spliceosome bound to the pyrimidine tract of an upstream U2-type intron [
,
].
Bacterial membrane-bound nickel-dependent hydrogenases [
,
,
] seem to be associated with a b-type cytochrome involved in electron transfer from hydrogen to oxygen. This cytochrome is a protein of about 28kDa that seems to have four transmembrane regions, which include several histidine residues that may be involved in coordination of the haem iron group. The gene coding for this cytochrome is adjacent to that coding for the large subunit of the hydrogenase. It has been assigned a variety of names in different species: hupC, hyaC, hydC or hoxZ.Every genome which contains a member of this family posesses a Ni/Fe hydrogenase according to Genome Properties (
), and most are gene clustered with other hydrogenase components. Some Ni/Fe hydrogenase-containing species lack a member of this family but contain other CytB homologues, which may substitute for it.
P-ATPases (also known as E1-E2 ATPases) ([intenz:3.6.3.-]) are found in bacteria and in a number of eukaryotic plasma membranes and organelles []. P-ATPases function to transport a variety of different compounds, including ions and phospholipids, across a membrane using ATP hydrolysis for energy. There are many different classes of P-ATPases, which transport specific types of ion: H+, Na
+, K
+, Mg
2+, Ca
2+, Ag
+and Ag
2+, Zn
2+, Co
2+, Pb
2+, Ni
2+, Cd
2+, Cu
+and Cu
2+. P-ATPases can be composed of one or two polypeptides, and can usually assume two main conformations called E1 and E2.
This entry represents cation-transporting P-type ATPase A (CtpA) and B (CtpB), which are bacterial proteins that belong to the IB subfamily of P-type ATPases [
,
]. CtpA has been identified as a copper-exporting P-type ATPase [].
SMG-1 plays a critical role in the mRNA surveillance mechanism known as non-sense mediated mRNA decay (NMD). NMD protects the cells from the accumulation of aberrant mRNAs with premature termination codons (PTCs) generated by genome mutations and by errors during transcription and splicing. SMG-1 phosphorylates Upf1, another central component of NMD, at the C terminus upon recognition of PTCs. The phosphorylation/dephosphorylation cycle of Upf1 is essential for promoting NMD [
]. In addition to its catalytic domain, SMG-1 contains a FATC (FRAP, ATM and TRRAP, C-terminal) domain at the C terminus. SMG-1 is a member of the phosphoinositide 3-kinase-related protein kinase (PIKK) subfamily. PIKKs have intrinsic serine/threonine kinase activity and are distinguished from other PKs by their unique catalytic domain, similar to that of lipid PI3K, and their large molecular weight (240-470kDa) [
]. This entry represents the SMG-1 catalytic domain.
This superfamily is represented by TorD. TorD is involved in the maturation of the the trimethylamine N-oxide reductase TorA (a DMSO reductase family member) in Escherichia coli [
]. TorA is a molybdenum-containing enzyme which requires the the insertion of a bis(molybdopterin guanine dinucleotide) molybdenum (bis(MGD)Mo) cofactor in its catalytic site to be active and translocated to the periplasm. TorD acts as a chaperone, binding to apoTorA and promoting efficient incorporation of the cofactor into the protein.
This superfamily also includes DmsD, which could be required for the biogenesis of DMSO reductase rather than for the targeting of DmsA to the inner membrane [
,
,
]. TorD and DmsD have a number of common features suggesting they function by using similar mechanisms. A major structural difference is that TorD is a domain-swapped dimer, while DmsD exists as a monomer [].
This entry represents a structural domain superfamily consisting of six helices in an irregular non-globular array; it also contains two small β-hairpins. This domain is found at the C terminus of the RNA-binding fertility inhibitor FinO that represses the conjugative transfer of F-like plasmids in Escherichia coli. FinO blocks the translation of TraJ, a positive activator of transcription of gene thereby protecting it from degradation, and catalyses FinP-TraJ mRNA hybridization. Interactions between these two RNAs are predicted to block the TraJ ribosomal binding site. FinO is largely helical, binds to its highest affinity binding site within FinP as a monomer, and contains two distinct RNA binding regions [
].This domain superfamily is also found as an N-terminal domain in ProQ, a protein required for full activation of the osmoprotectant transporter ProP in Escherichia coli [
].
The cocaine and amphetamine regulated transcript (CART) is a brain-localised peptide that acts as a satiety factor in appetite regulation. CART was found to inhibit both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. CART is regulated by leptin in the hypothalamus, and can be transcriptionally induced after cocaine or amphetamine administration [
]. CART has also been suggested to activate ERK1 through interaction with a specific G-protein coupled receptor []. Posttranslational processing of CART produces an N-terminal CART peptide and a C-terminal CART peptide. The C-terminal CART peptide has been isolated from the hypothalamus, nucleus accumbens, and the anterior pituitary lobe in rats. C-terminal CART is the biologically active part of the molecule affecting food intake. The structure of C-terminal CART consists of a disulphide-bound fold containing a β-hairpin and two adjacent disulphide bridges [].
This entry represents coagulation factors V and VIII, as well as other members of the multicopper oxidase family including the functionally similar venom prothrombin activator subunits, and the possible ferroxidase, hephaestin.Mammalian coagulation factors V and VIII play analogous roles as non-enzymatic cofactors in the activation of prothrombin and factor X, respectively. They are proteolytically activated by thrombin and inactivated by activated protein C (APC).The structures of factor V and VIII have been determined [
,
]. The domain architecture of their precursor molecules can be represented as A1-A2-B-A3-C1-C2. The A domains are diverged versions of the multicopper oxidase domain (). The B domain is highly variable and is removed during activation to yield non-covalently-associated heavy and light chains; this domain in mammalian factor V contains multiple copies of a 9-residue repeat (see
). The C domains (
) promote membrane binding.
The cocaine and amphetamine regulated transcript (CART) is a brain-localised peptide that acts as a satiety factor in appetite regulation. CART was found to inhibit both normal and starvation-induced feeding, and completely blocks the feeding response induced by neuropeptide Y. CART is regulated by leptin in the hypothalamus, and can be transcriptionally induced after cocaine or amphetamine administration [
]. CART has also been suggested to activate ERK1 through interaction with a specific G-protein coupled receptor []. Posttranslational processing of CART produces an N-terminal CART peptide and a C-terminal CART peptide. The C-terminal CART peptide has been isolated from the hypothalamus, nucleus accumbens, and the anterior pituitary lobe in rats. C-terminal CART is the biologically active part of the molecule affecting food intake. The structure of C-terminal CART consists of a disulphide-bound fold containing a β-hairpin and two adjacent disulphide bridges [].
The eukaryotic Sm proteins (B/B', D1, D2, D3, E, F and G) assemble into a hetero-heptameric ring around the Sm site of the 2,2,7-trimethyl guanosine (m3G) capped U1, U2, U4 and U5 snRNAs (Sm snRNAs) forming the core of the snRNP particle. The snRNP particle, in turn, assembles with other components onto the pre-mRNA to form the spliceosome which is responsible for the excision of introns and the ligation of exons. Members of this family share a highly conserved Sm fold containing an N-terminal helix followed by a strongly bent five-stranded antiparallel β-sheet [,
,
].Sm subunit D1 heterodimerizes with subunit D2 and three such heterodimers form a hexameric ring structure with alternating D1 and D2 subunits. The D1 - D2 heterodimer also assembles into a heptameric ring containing DB, D3, E, F, and G subunits [
,
].
This entry represents a family of bacterial and archaeal uridine phosphorylases unrelated to the mammalian enzymes of the same name. The Escherichia coli [
], Salmonella [] and Klebsiella [] genes have been characterised. Sequences from Clostridium, Streptomyces, Treponema, Aeropyrum and Pyrobaculum are also included in this family, but it does not include related sequences from Halobacterium, which are more distantly related and represent enzymes with a slightly different substrate specificity. Also distantly related is a clade of archaeal sequences which are related to the DeoD family of inosine phosphorylases () as they are to these uridine phosphorylases. This clade includes a characterised protein from Sulfolobus solfataricus which has been misnamed as a methylthioadenosine phosphorylase, but which acts on inosine and guanosine - it is unclear whether uridine has been evaluated as a substrate [
].
Tumor necrosis factor receptor superfamily member 26 (TNFRSF26), also known as tumor necrosis factor receptor homologue 3 (TNFRH3) or TNFRSF24, is predominantly expressed in embryos and lymphoid cell types, along with its closely related TNFRSF22 and TNFRSF23 orthologues, and is developmentally regulated. These three
TNFSFRs genes are present in the mouse and rat, but absent in humans []. Unlike TNFRSF22/23, TNFRSF26 does not serve as a TRAIL decoy receptor; it remains an orphan receptor [].This entry represents the N-terminal domain of TNFRSF26 and the TNFRSF22 and TNFRSF23 orthologues. TNF-receptors are modular proteins. The N-terminal extracellular part contains a cysteine-rich region responsible for ligand-binding. This region is composed of small modules of about 40 residues containing 6 conserved cysteines; the number and type of modules can vary in different members of the family [
,
,
].
The polo-like Ser/Thr kinases (Plk1, Plk2/Snk, Plk3/Prk/Fnk, Plk4/Sak, and the inactive kinase Plk5) play various roles in cytokinesis and mitosis. At their C terminus, they contain a tandemly repeated polo-box domain (PBD) (in the case of Plk4, a tandem repeat of cryptic PBDs is found in the middle of the protein followed by a C-terminal single repeat), which appears to be involved in autoinhibition and in mediating the subcellular localization. The latter may be controlled via interactions between the polo-box domain and phospho-peptide motifs. The phosphopeptide binding site is formed at the interface between the two tandemly repeated PBDs. The PBDs of Plk4/Sak appear unique in participating in homodimer interactions, though it is not clear whether and how they interact with phosphopeptides [,
,
,
,
,
].This entry represents the second polo-box domain found in Plk1, Plk2 and Plk3.
The polo-like Ser/Thr kinases (Plk1, Plk2/Snk, Plk3/Prk/Fnk, Plk4/Sak, and the inactive kinase Plk5) play various roles in cytokinesis and mitosis. At their C terminus, they contain a tandemly repeated polo-box domain (PBD) (in the case of Plk4, a tandem repeat of cryptic PBDs is found in the middle of the protein followed by a C-terminal single repeat), which appears to be involved in autoinhibition and in mediating the subcellular localization. The latter may be controlled via interactions between the polo-box domain and phospho-peptide motifs. The phosphopeptide binding site is formed at the interface between the two tandemly repeated PBDs. The PBDs of Plk4/Sak appear unique in participating in homodimer interactions, though it is not clear whether and how they interact with phosphopeptides [
,
,
,
,
,
].
This entry represents the C-terminal (third) polo-box domain of Plk4.
The polo-like Ser/Thr kinases (Plk1, Plk2/Snk, Plk3/Prk/Fnk, Plk4/Sak, and the inactive kinase Plk5) play various roles in cytokinesis and mitosis. At their C terminus, they contain a tandemly repeated polo-box domain (PBD) (in the case of Plk4, a tandem repeat of cryptic PBDs is found in the middle of the protein followed by a C-terminal single repeat), which appears to be involved in autoinhibition and in mediating the subcellular localization. The latter may be controlled via interactions between the polo-box domain and phospho-peptide motifs. The phosphopeptide binding site is formed at the interface between the two tandemly repeated PBDs. The PBDs of Plk4/Sak appear unique in participating in homodimer interactions, though it is not clear whether and how they interact with phosphopeptides [,
,
,
,
,
].This entry represents the first polo-box domain found in Plk1, Plk2, Plk3, and Plk5.
NrpR is an transcriptional repressor of nitrogen assimilation genes found primarily in Euryarchaeota [
]. In the thermophilic archaeon Methanocaldococcus jannaschii it consists of a putative N-terminal winged helix-turn-helix (wHTH) domain used for DNA binding followed by two NrpR regulatory domains (NRD1 and NRD2) that sense and bind 2-oxoglutarate []. In different organisms, NrpR proteins can vary on how many NrpR regulatory domains they contain and in their configuration. They can contain two NrpR domains, or one NrpR domain with or without the N-terminal HTH motif [].This superfamily describes the NRD domain, which consists of two halves. The helices from each half are located near the centre of the NRD domain forming an α-helical layer onto which the β-sheets are sandwiched from either side. A large cleft is formed between the two halves of the NRD regulatory domain [
].
Interleukins (IL) are a group of cytokines that play an important role in the immune system. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells. Interleukin-17 (IL-17) is a potent proinflammatory cytokine produced by activated memory T cells [
]. The IL-17 family (of which there are 6 known members, termed IL-17A to IL-17F) is thought to represent a distinct signalling system that appears to have been highly conserved across vertebrate evolution []. Family members play an active role in inflammatory diseases, autoimmune diseases and cancer []. This entry represents interleukin-17 family IL-17A to IL-17F. Interleukin-17E has been renamed as interleukin-25 (IL-25). The orthologue from the nematode Caenorhabditis elegans, known as interleukin cytokine-related protein 17.1, is a neuromodulator of sensory responses, and the ligand for the receptor complex composed of ilcr-1 and ilcr-2 [
].
The sugar isomerase (SIS) domain is a phosphosugar-binding module that is found in a variety of eubacterial, archaebacterial and eukaryotic proteins
that have a role in phosphosugar isomerization or regulation []. In enzymes, the SIS domain can have a catalytic function as an isomerase and bind to phosphorylated sugars. In bacterial transcriptional regulators of the rpiR family, the domain seems to bind substrates implicated in the genes for sugar metabolism that are controlled by the regulator. The SIS domain is found in one or two copies and can be linked to additional domains, such as helix-turn-helix (HTH), CBS, glutamineamidotransferases type 2, or phosphopantetheine-attachment [
,
].The SIS domain has an α-β structure and is dominated by a five-stranded parallel β-sheet flanked on either side by α-helices forming a three-layer α-β-α sandwich [
]. The fold shows similarities to that of glucose-6-phosphate isomerase.
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 [
].
Aldehyde oxidase (
) catalyses the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide. The enzyme is a homodimer, and requires FAD, molybdenum and two 2FE-2S clusters as cofactors. Xanthine dehydrogenase (
) catalyses the hydrogenation of xanthine to urate, and also requires FAD, molybdenum and two 2FE-2S clusters as cofactors. This activity is often found in a bifunctional enzyme with xanthine oxidase (
) activity too. The enzyme can be converted from the dehydrogenase form to the oxidase form irreversibly by proteolysis or reversibly through oxidation of sulphydryl groups.
The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain [
,
]. The core structure of this domain has a β-β-α-β-BETA-beta-alpha fold and contains a β-hammerhead motif similar to that in barrel-sandwich hybrids.
This entry represents the N-terminal region of the eukaryotic epoxide hydrolase protein. Epoxide hydrolases (
) comprise a group of functionally related enzymes that catalyse the addition of water to oxirane compounds (epoxides), thereby usually generating vicinal trans-diols. EHs have been found in all types of living organisms, including mammals, invertebrates, plants, fungi and bacteria. In animals, the major interest in EH is directed towards their detoxification capacity for epoxides since they are important safeguards against the cytotoxic and genotoxic potential of oxirane derivatives that are often reactive electrophiles because of the high tension of the three-membered ring system and the strong polarisation of the C--O bonds. This is of significant relevance because epoxides are frequent intermediary metabolites, which arise during the biotransformation of foreign compounds [
]. This domain is often found in conjunction with .
Terminase large subunit (TerL) from bacteriophages and evolutionarily related viruses, is an important component of the DNA packing machinery and comprises an ATPase domain, which powers DNA translocation and a nuclease domain that cuts concatemeric DNA [
,
]. TerL forms pentamers in which the ATPase domains form a ring distal to the capsid. This is the ATPase domain which contains a C-terminal subdomain that sits above the ATPase active site, called the "Lid subdomain"with reference to analogous lid subdomains found in other ATPases [
]. It contains a hydrophobic patch (Trp and Tyr residues) that mediates critical interactions in the interface between adjacent ATPase subunits and assists the positioning of the arginine finger residue that catalyses ATP hydrolysis [,
]. This domain is also found in uncharacterised proteins encoded by bacterial prophages, including YmfN from Escherichia coli.
Trypanothione reductase from Leishmania, and African and South American trypanosomes, has been purified and characterised [
]. The enzymes have similar physical, mechanistic and kinetic properties, and are members of the flavoprotein disulphide oxidoreductase family. Trypanothione is the parasite analogue of glutathione, hence this enzyme is equivalent to glutathione reductase. It catalyses the reaction:NADPH + trypanothione = NADP(+) + reduced trypanothioneTrypanothione reductase shows pronounced specificty for its disulphide substrates, trypanothione disulphide or glutathionylspermidine disulphide. The 3D structure of the enzyme has been determined and its mode of substrate binding revealed in detail [
], offering hope for the design of drugs to combat Chagas disease. The structure belongs to the alpha+beta class, i.e. with mainly anti-parallel β-sheets separated by alpha and beta regions. It contains an α-β sandwich characteristic of FAD/NAD-linked reductases and a C-terminal dimerisation domain.
This entry represents the C-terminal catalytic domain of the deadenylase CCR4a, also known as CCR4-NOT transcription complex subunit 6 (CNOT6). CCR4 belongs to the large EEP (exonuclease/endonuclease/phosphatase) superfamily that contains functionally diverse enzymes that share a common catalytic mechanism of cleaving phosphodiester bonds. In S. cerevisiae, Ccr4 is the major deadenylase subunit of the CCR4-NOT transcription complex, which contains two deadenylase subunits and several noncatalytic subunits [
,
].There are two vertebrate CCR4 proteins, CCR4a and CCR4b (also called CNOT6-like or CNOT6L). CCR4a associates with other components, such as CNOT1-3 and Caf1, to form a CCR4-NOT multisubunit complex, which regulates transcription and mRNA degradation [
]. CCR4a is a component of P-bodies and is necessary for foci formation of various P-body components [,
]. It also plays a role in cellular responses to DNA damage, by regulating Chk2 activity [].
This entry represents the bHLH domain found in a group of transcription factors from plants, including IBH1 (ILI1-BINDING BHLH 1), IBHL1 and related proteins such as UPBEAT1, PAR1 and PAR2 from Arabidopsis. IBH1 (also known as AtbHLH158) and IBHL1 are atypical and probable non DNA-binding bHLH transcription factors that act as transcriptional repressors that negatively regulate cell and organ elongation in response to gibberellin (GA) and brassinosteroid (BR) signaling [
,
]. IBH1 forms heterodimer with BHLH49, thus inhibiting DNA binding of BHLH49. Another atypical transcription factors included in this entry are PAR1 (also termed AtbHLH165) and PAR2 (also termed AtbHLH166) that act as negative regulators of a variety of shade avoidance syndrome (SAS) responses [,
]. UPBEAT1 (also known as AtbHLH151 or EN 146), modulates the balance between cellular proliferation and differentiation in root growth [].
Histatins are small molecular weight proteins produced by the human salivary glands that exhibit antifungal and antibacterial activities [
]. They are also components of the acquired enamel pellicle (AEP) []. Histatins 1 and 3 are full-length peptides of 38 and 32 amino acid residues respectively; other characterised members of the histatin family are proteolytic products formed during secretion [,
,
]. The predominant histatins are histatin 1, 3, and 5; histatin 5 is a proteolytic product of histatin 3.Statherin is a 43-residue peptide, secreted by parotid and submandibular glands. It is a multifunctional molecule that prevents calcium phosphate precipitation in saliva, thus maintaining a high calcium and phosphate levels [,
]. Moreover, statherin and its C-terminal fragments inhibit the growth of anaerobic bacteria from the oral cavity []. Statherin and histatin 1 reduce Streptococcus mutans adhesion onto hydroxyapatite surfaces [].
This superfamily includes several eukaryotic Sin3 associated polypeptide p18 (SAP18) sequences. SAP18 is known to be a component of the Sin3-containing complex which is responsible for the repression of transcription via the modification of histone polypeptides [
]. SAP18 (UBL domain) is one of the three three ASAP subunits (along with Acinus (β-hairpin motif) and RNPS1 (RRM domain)) that play a role in programmed cell death, transcriptional regulation, pre-mRNA splicing and mRNA quality control [,
]. The ASAP complex interacts with the exon-junction complex (EJC), a messenger ribonucleoprotein complex involved in post-transcriptional regulation [].The high degree of evolutionary conservation and the fortuitous crystal contacts at the α-β groove suggest that this surface of SAP18 is a hot spot for interactions. Possible binding partners targeting this surface of SAP18 are transcription factors (such as Bicoid and Kruppel) and/or Sin3a-HDAC subunits.
This domain is often repeated twice within the same polypeptide, as is observed in Archaea, Thermus, Sphingobacteria [
] and Fungi. In the fungal sequences, this tandem domain pair is observed as the N-terminal half of a bifunctional protein [], where it has been characterised as a lycopene beta-cyclase and the C-terminal half is a phytoene synthetase. In Myxococcus and Actinobacterial genomes this domain appears as a single polypeptide, tandemly repeated and usually in a genomic context consistent with a role in carotenoid biosynthesis. One member of this family has been annotated as a lycopene beta-cyclase []. The domain is generally hydrophobic with a number of predicted membrane spanning segments and contains a distinctive motif (hPhEEhhhhhh). In certain sequences one of either the proline or glutamates may vary, but always one of the tandem pair appear to match this canonical sequence exactly.
This entry represents glutaminyl cyclases (QC), which are a subfamily of the peptidase M28 family. Glutaminyl cyclase (QC, QPCT, glutaminyl-peptide cyclotransferase) [
,
] and iso-glutaminyl cyclase (QPCTL, isoQC) [] catalyze the formation of an N-terminal pyroglutamate (pGlu) residue from a glutaminyl or glutamyl residue. QC and isoQC are closely related single-zinc metalloenzymes that exhibit nearly identical substrate specificity in vitro []. The major difference refers to subcellular localization: QC is secreted from expressing cells; isoQC is a resident enzyme of the Golgi complex []. In humans, QCs are involved in several pathological conditions, such as Alzheimer disease [,
].Human pituitary glutaminyl cyclase shares a common fold and active site residues with and bacterial zinc aminopeptidase. In contrast to the aminopeptidase, however, QC does not appear to require zinc for enzymatic activity [
].This entry also includes peptidase_M28 domain-containing proteins from bacteria.
Metazoan granulins [
] are a family of cysteine-rich peptides of about 6 kDa which may have multiple biological activity. A precursor protein (known as acrogranin) potentially encodes seven different forms of granulin (grnA to grnG) which are probably released by post-translational proteolytic processing. Granulins are evolutionary related to PMP-D1, a peptide extracted from the pars intercerebralis of migratory locusts []. In humans, Progranulin (PGRN) is of 7.5 granulin repeats encoded by the granulin (GRN) gene. It is a secreted growth factor implicated in a multitude of processes ranging from regulation of inflammation to wound healing and tumorigenesis []. Progranulin can be processed in the lysosome through the actions of cathepsins []. Haploinsufficiency of progranulin causes frontotemporal lobar degeneration (FTLD), and complete loss of PGRN leads to a lysosomal storage disorder, neuronal ceroid lipofuscinosis (NCL) [].
RelA-associated inhibitor, also known as iASPP, is an oncoprotein that inhibits the apoptotic transactivation potential of p53 [
,
,
]. It is upregulated in human breast cancers expressing wild-type p53 [], in acute leukemias regardless of the p53 mutation status [], as well as in ovarian cancer where it is associated with poor patient outcome and chemoresistance []. iASPP is also a binding partner and negative regulator of p65RelA, which promotes cell proliferation and inhibits apoptosis; p65RelA has the opposite effect on cell growth compared to the p53 family []. It contains a proline-rich region, four ankyrin (ANK) repeats, and an SH3 domain at its C-terminal half. The SH3 domain and the ANK repeats of iASPP contribute to the p53 binding site; they bind to the DNA binding domain of p53.This entry represents the SH3 domain found in iASPP.
GPCR family 2, glucagon-like peptide 2 receptor, transmembrane domain
Type:
Domain
Description:
Glucagon-like peptide 2 (GLP2) acts through G protein-coupled receptor GLP2R and plays a physiological role in the control of food intake and glucose homeostasis. It promotes intestinal epithelial homeostasis and function, enhances intestinal nutrient absorption and blood flow and assists gut immune defense [
]. GLP2R belongs to the B1 (or secretin-like) subfamily of class B GPCRs, which includes receptors for polypeptide hormones of 27-141 amino acid residues such as secretin, calcitonin gene-related peptide, parathyroid hormone (PTH), and corticotropin-releasing factor [,
]. It is not only expressed in nutrient-sensing endocrine cells (such as enteroendocrine cells and pancreatic alpha-cells), but also in neurons [,
,
]. GLP2R in hypothalamic POMC neurons is required for promoting hepatic insulin sensitivity and glycemic control. Through GLP2R-p85alpha interaction, GLP2 activates PI3K-Akt-FoxO1 signaling in POMC neurons [].This entry represents the transmembrane region of GLP2R [
].
Protective antigen (PA) is the central component of the three-part protein toxin secreted by Bacillus anthracis, the organism responsible for anthrax. Homologues of PA have been found in several spore-forming Gram-positive bacteria, and share the ability to translocate toxic enzymes into the host cytosol. The PA monomer is organised mainly into antiparallel β-sheets and has four domains: an N-terminal domain (domain 1) containing two calcium ions and the cleavage site for activating proteases; a heptamerisation domain (domain 2) containing a large flexible loop implicated in membrane insertion; a small domain of unknown function (domain 3); and a carboxy-terminal receptor-binding domain (domain 4) [
]. This superfamily represents the domain 4 of PA, which has an immunoglobulin-like fold. Domain 4 plays a key role in cellular receptor recognition, as well as in pH-dependent pore formation [
].
This domain can be found in the phage RepB primase and the C terminus of the E. coli MobA protein. RepB primase is a DNA-primase produced by P4-like phages. It is a zinc-independent primase unlike Pri-type primases. It takes up a dumbbell shape consisting of an N-terminal catalytic domain separated by a long α-helix plus tether and a C-terminal helical-bundle domain. Primases are necessary for phage replication. These primases recognise both ssiA and ssiB, ie only 1 single-stranded primase initiation site on each strand, independently of each other and then synthesize primers that are elongated by DNA polymerase III. The phage is thus replicated exclusively in leading strand mode [
].MobA contains a N-terminal DNA relaxase domain and a C-terminal DNA primase domain. It is part of the relaxosome complex that is responsible for plasmid transfer during conjugation [
].
Hypoxia-inducible factor 1-alpha inhibitor, domain II
Type:
Homologous_superfamily
Description:
This superfamily represents the domain II of the hypoxia-inducible factor 1-alpha inhibitor, which is composed of a central β-barrel surrounded by eight α-helices. It consists of two domains. Domain I runs from N terminus to residue 300 and is mainly composed of the central β-barrel and six α-helices surrounding them. Domain II (residues 301-349) comprising two consecutive α-helices stretches away from domain I. Domain II, which is completely missing in all known structures of the dioxygenase family, forms strong interactions with the same region of the 2-fold symmetry related molecule [
,
,
]. Hypoxia-inducible factor 1-alpha inhibitor hydroxylates a specific Asn residue in the C-terminal transactivation domain (CAD) of HIF-1 alpha. The hydroxylation prevents interaction of HIF-1 with transcriptional coactivators. It also hydroxylates specific Asn, Asp and His residues within ankyrin repeat domain-containing proteins [
,
,
].
Latrophilins are a family of secretin-like GPCRs that can be subdivided
into 3 subtypes: Latrophilin-1 (LPH1), -2 (LPH2), and -3 (LPH3). LPH1, also known as Adhesion G protein-coupled receptor L1 (Adgrl1), is a brain-specific calcium independent receptor of alpha-latrotoxin (LTX), a neurotoxin present in black widow spider venom which triggers massive exocytosis from presynaptic nerve terminals [,
]. It is the affinity of this form of the receptor for LTX that gives the family its name.
Two endogenous ligands for latrophilins have been described, teneurin-2 [
] and FLRT3 []. LPH1 has been shown to bind Lasso (a splice variant of teneurin-2). LPH1 and Lasso interact across intercellular and synaptic junctions, suggesting an involvement in synaptic functions []. Latrophilins are potential synaptic cell-adhesion molecules that interact trans-synaptically with teneurins and FLRTs []. This entry represents the seven-transmembrane helix domain of LPH1.
Site-specific DNA-methyltransferase, N-6 adenine-specific DNA methylase (
) and cytosine-N4-specific (
) are enzymes that specifically methylate the amino group at the C-4 position of cytosines and the N-6 position of adenine in DNA. In prokaryotes, the major role of DNA methylation is to protect host DNA against degradation by restriction enzymes. There are two major classes
of DNA methyltransferase that differ in the nature of the modificationsthey effect. The members of one class (C-MTases) methylate a ring carbon and
form C5-methylcytosine and members of the second class (N-MTases) methylateexocyclic nitrogens and form either N4-methylcytosine (N4-MTases) or
N6-methyladenine (N6-MTases). Both classes utilise the cofactorS-adenosyl-L-methionine (SAM) as the methyl donor and are active as monomeric enzymes. These proteins show three domains, two of them are conserved across multiple kingdoms (SAM binding and the catalytic domain) [
,
].
Several agrobacteria cause neoplastic diseases in plants, including crown gall disease (Agrobacterium tumefaciens) and hairy root disease (Agrobacterium rhizogenes). The mechanism involves transfer via infective plasmids and subsequent expression of both oncogenes and genes for the synthesis of opines, which can be specifically used as nutrients by the invading bacteria [
]. Opines are low molecular weight amino acid and sugar phosphate derivatives, e.g., octopine, agropine, and mannopine. The proteins in this group are products of the mas1genes (and homologues) encoding the reductase that produces mannopine from deoxyfructosylglutamine. Subsequently, mannopine can be lactonized to form agropine. The C-terminal short chain dehydrogenase domain is coupled with an N-terminal phosphoglycerate mutase family domain (
), the role of which is unknown [
]. Sequences reported from Ti plasmid pTiC58 are missing half [,
] or all of the N-terminal domain.
E3 ubiquitin-protein ligase AMFR, Ube2g2-binding region
Type:
Domain
Description:
The activity of RING finger ubiquitin ligases (E3) is dependent on their ability to facilitate transfer of ubiquitin from ubiquitin-conjugating enzymes (E2) to substrates. The G2BR domain within the E3 ubiquitin-protein ligase AMFR (also known as gp78) binds selectively and with high affinity to the E2 Ube2g2. Binding to the G2BR results in conformational changes in Ube2g2 that affect ubiquitin loading. The Ube2g2-G2BR interaction also causes a 50-fold increase in affinity between the E2 and RING finger. Hence, the Ube2g2-binding region (G2BR) is required for the function of gp78. In yeast, Ubc7p, the ortholog of Ube2g2, is recruited by Cue1p to the ER membrane. Cue1p directly binds Ubc7p through a stretch of 50 aa domain analogous to G2BR, i.e. suggesting that this domain which activates ERAD and Hrd1p stimulating ubiquitylation, might be the yeast equivalent of the G2BR domain [
,
,
].
Sporulation initiation phospho-transferase B or SpoOB is part of a phospho-relay that initiates sporulation in Bacillus subtilis. Spo0B is a two-domain protein consisting of an N-terminal α-helical hairpin domain and a C-terminal alpha/beta domain. Two subunits of Spo0B dimerise by a parallel association of helical hairpins to form a novel four-helix bundle from which the active histidine - involved in the auto-phosphorylation - protrudes. In the phospho-relay, the signal-receptor histidine kinases are dephosphorylated by a common response regulator, Spo0F. Spo0B then takes phosphorylated Spo0F as substrate thereby mediating the transfer of a phosphoryl group to Spo0A, the ultimate transcription factor. The exact function of this α-helical domain is not known; it does not always occur just as the N-terminal domain of SPOB_ab,
. SCOP describes this domain as a histidine kinase-like fold lacking the kinase ATP-binding site [
].
This domain, consisting of the distinct N-terminal PRY subdomain followed by the SPRY subdomain, is found at the C terminus of butyrophilin family 3A (BTN3A). Duplication events have led to three paralogues in primates: BTN3A1, BTN3A2, and BTN3A3. BTNs belong to receptor glycoproteins of immunoglobulin (Ig) superfamily, characterised by the presence of extracellular Ig-like domains (IgV and/or IgC). BTN3 transcripts are ubiquitously present in all immune cells (T cells, B cells, NK cells, monocytes, dendritic cells, and hematopoietic precursors) with different expression levels; BTN3A1 and BTN3A2 are expressed mainly by CD4+ and CD8+ T cells, BTN3A2 is the major form expressed in NK cells, and BTN3A3 is poorly expressed in these immune cells [
,
].The PRY/SPRY domain of the BTN3A1 isoform mediates phosphoantigen (pAg)-induced activation by binding directly to the pAg [
,
,
].
A member of the nucleic acid/nucleotide deaminase superfamily prototyped by OTT_1508 from the intracellular bacterial pathogen Orientia tsutsugamushi ([
]. Members of this family are present in a wide phyletic range of bacteria,including several intracellular parasites and eukaryotes such as fungi, Leishmania, Selaginella, and some apicomplexa. In bacteria, these deaminases are predicted to function as toxins in bacterial polymorphic toxin systems []. Versions in intracellular bacteria lack immunity proteins and are likely to be deployed against their eukaryotic hosts. Eukaryotic versions are predicted to function as nucleic acid (either DNA or RNA) deaminases. Among eukaryotes, some fungi show lineage-specific expansions of this family. Many fungal versions are fused to a distinct N-terminal globular domain. Various fungal versions are fused to domains involved in chromatin function. Apicomplexan versions are fused to tRNA guanine transglycosylase domain [
].
Cathepsin D (
and MEROPS identifier A01.009) is an aspartic endopeptidase located in the lysosome of animal cells. It is synthesized as an inactive precursor and activated in the lysosome, either autolytically or by other lysosomal peptidases [
]. Its optimum pH is ~3.5 []. Quantitative N-terminal proteomics has been used to study the specificity of the enzyme []. Although primarily thought to be involved in lysosomal catabolism of proteins, knockout of the mouse CATD gene is neonatally fatal and associated with numerous defects [,
]. Cathepsin D has been shown to induce apoptosis [,
,
]. Procathepsin D is also secreted in some cancers, where it can be activated at the acidic pH of the tumour microenvironment and promote the growth of cancer tissue or metastasis by degradation of extracellular matrix [], or act as a mitogen [].
The arginine dihydrolase (AD) pathway is found in many prokaryotes and some
primitive eukaryotes. The three- enzyme anaerobic pathway breaks down L-arginine to form 1 mol of ATP, carbon
dioxide and ammonia. In simpler bacteria, the first enzyme, arginine deiminase, can account for up to 10% of total cell protein [
].Carbamate kinase is involved in the last step of the AD pathway, converting
carbamoyl phosphate and ADP into ammonia, carbon dioxide and ATP []. Thesecond step of the pathway involves the degradation of L-citrulline to
carbamoyl phosphate and L-ornithine, using ornithine carbamoyltransferase [].The crystal structure of Enterococcus faecium carbamate
kinase has been determined to 2.8A resolution []. The enzyme exists as ahomodimer of two 33kDa subunits. The hallmark of the dimer is a 16-stranded
β-sheet, surrounded by α-helices. Each subunit contains an activesite within a large crevice.
Methane monooxygenases (
) catalyse the oxidation of methane to methanol in the presence of oxygen and NADH in methanotrophs. It has a broad specificity, hydroxylating many alkanes, and converting alkenes into the corresponding epoxides. In additional reactions, CO is oxidized to CO2, ammonia is oxidized to hydroxylamine, and some aromatic compounds and cyclic alkanes can also be hydroxylated, although more slowly. In Methylococcus capsulatus there are two forms of the enzyme, a soluble and a membrane-bound type. The soluble form consists of 3 components, A, B and C. Protein A is made up of 3 chains, alpha, beta and gamma.
Structurally, the gamma chain of methane monooxygenases contain two domains, each consisting of a three helices arranged in an open bundle topology [
,
]. This superfamily represents one of two α-bundle domains found in the gamma chain.
Methane monooxygenases (
) catalyse the oxidation of methane to methanol in the presence of oxygen and NADH in methanotrophs. It has a broad specificity, hydroxylating many alkanes, and converting alkenes into the corresponding epoxides. In additional reactions, CO is oxidized to CO2, ammonia is oxidized to hydroxylamine, and some aromatic compounds and cyclic alkanes can also be hydroxylated, although more slowly. In Methylococcus capsulatus there are two forms of the enzyme, a soluble and a membrane-bound type. The soluble form consists of 3 components, A, B and C. Protein A is made up of 3 chains, alpha, beta and gamma.
Structurally, the gamma chain of methane monooxygenases contain two domains, each consisting of a three helices arranged in an open bundle topology [
,
]. This superfamily represents one of two α-bundle domains found in the gamma chain.
This domain is considered a double homeodomain, termed HOCHOB, present in the C. elegans genome. Proteins containing this domain include CEH-91/92/93 that share extended sequence similarity with each other upstream of their typical HDs (Homeodomains). CEH-92 has three copies of this domain. The domain consists of two divergent HDs that are separated by a linker of about 17 residues. The linker has a number of conserved positions, two of which are cysteine residues suggesting that they could be involved in metal binding. Hence, the name HOCHOB (Homeobox-cysteine loop-homeobox). Furthermore, there are two conserved histidine residues, one in each HD (in CEH-91 displaced by two positions), and there is also a conserved aspartic acid. It is speculated that the HOCHOB domain is an evolutionary novelty that is derived from two HDs and may have gained metal-binding capacity [].
Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate [
]. These enzymes catalyze the transfer of a sulfo group from the sulfo donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), to the 3-OH position of a glucosamine unit of heparin sulfate (HS). 3-O-sulfation is critically important for anticoagulant activity [
]. The key control of anticoagulant HS synthesis is regulation of the expression of 3-O-sulfotransferase isoforms 1 and 5 (3-OST-1 and 3-OST-5). 3-O-sulfation is also involved in the regulation of neural development [,
,
].3-OST proteins exhibit similarity with the heparan biosynthetic enzyme NST (bifunctional HS N-deacetylase/N-sulfotransferase). It appears that a common sulfotransferase structure is shared by these two types of heparan biosynthetic enzyme [
]. The bifunctional enzyme catalyzes both the N-deacetylation and the N-sulfation of glucosamine (GlcNAc) of the glycosaminoglycan in HS [].
This family consists of muconate cycloisomerase (or Muconate Lactonizing Enzyme (MLE);
) and chloromuconate cycloisomerase (or chloromuconate lactonizing enzymes (Cl-MLEs);
), enzymes that often overlap in specificity. It does not include more distantly related proteins such as mandelate racemase (
).
MLE, a homooctameric enzyme, catalyses the conversion of cis,cis-muconate to muconolactone in the catechol branch of the beta-ketoadipate pathway [
,
]. This pathway is used in soil microbes to breakdown lignin-derived aromatics, catechol and protocatechuate, to citric acid cycle intermediates. Some bacterial species are also capable of dehalogenating chloroaromatic compounds by the action of Cl-MLEs. MLEs are members of the enolase superfamily characterized by the presence of an enolate anion intermediate which is generated by abstraction of the alpha-proton of the carboxylate substrate by an active site residue and that is stabilized by coordination to the essential Mg2+ ion [,
].
The phosphotyrosine-binding domain (PTB, also phosphotyrosine-interaction or PI domain) of tensin tends to be found at the C terminus. Tensin is a multi-domain protein that binds to actin filaments and functions as a focal-adhesion molecule (focal adhesions are regions of plasma membrane through which cells attach to the extracellular matrix). Human tensin has actin-binding sites, an SH2 (
) domain and a region similar to the tumour suppressor PTEN [
]. The PTB domain interacts with the cytoplasmic tails of beta integrin by binding to an NPXY motif [
]. The PTB domain is also found in the epidermal growth factor receptor kinase substrate 8 (EPS8).PTB domains are classified into three groups: phosphotyrosine-dependent Shc-like, phosphotyrosine-dependent IRS-like, and phosphotyrosine-independent Dab-like PTB domains [
].This entry refers to the PTB domain found in Tensin, part of the Dab-like subgroup.
This entry represents the iron-sulfur cluster-binding SPASM domain of anSME and similar proteins from prokaryotes.Anaerobic sulfatase maturating enzyme (anSME) is a radical S-adenosylmethionine (SAM) enzyme that catalyses, under anaerobic conditions, the co- or post-translational modification of arylsulfatases to form a catalytically essential formylglycine (FGly) residue to perform their hydrolysis function, removing sulfate groups from a wide array of substrates [,
,
,
,
,
,
]. Radical SAM enzymes are characterized by a conserved CxxxCxxC motif, which coordinates the conserved iron-sulfur cluster that is involved in the reductive cleavage of SAM and generates a 5'-deoxyadenosyl radical, which in turn abstracts a hydrogen from the appropriately positioned carbon atom of the substrate. Radical SAM (RS) enzymes with a C-terminal SPASM domain contain at least one other iron-sulfur cluster; anSME contains two auxillary 4Fe-4S clusters in its SPASM domain [].
Fructose bisphosphatase (FBPase)
is a critical regulatory enzyme in gluconeogenesis that catalyses the removal of 1-phosphate from fructose 1,6-bis-phosphate to form fructose 6-phosphate [
,
]. It is involved in many different metabolic pathways and found in most organisms. FBPase requires metal ions for catalysis (Mg2+and Mn
2+being preferred) and the enzyme is potently inhibited by Li
+. The fold of fructose-1,6-bisphosphatase was noted to be identical to that of inositol-1-phosphatase (IMPase) [
]. Inositol polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif (Asp-Pro-Ile/Leu-Asp-Gly/Ser-Thr/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial and yeast IMPase homologues. It has been suggested that these proteins define an ancient structurally conserved family involved in diverse metabolic pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone metabolism [].
Riboflavin is converted into catalytically active cofactors (FAD and FMN) by the actions of riboflavin kinase (
), which converts it into FMN, and FAD synthetase (
), which adenylates FMN to FAD. Eukaryotes usually have two separate enzymes, while most prokaryotes have a single bifunctional protein that can carry out both catalyses, although exceptions occur in both cases. While eukaryotic monofunctional riboflavin kinase is orthologous to the bifunctional prokaryotic enzyme [
], the monofunctional FAD synthetase differs from its prokaryotic counterpart, and is instead related to the PAPS-reductase family []. The bacterial FAD synthetase that is part of the bifunctional enzyme has remote similarity to nucleotidyl transferases and, hence, it may be involved in the adenylylation reaction of FAD synthetases [].This entry represents riboflavin kinase, which occurs as part of a bifunctional enzyme or a stand-alone enzyme.
Ribulose-phosphate 3-epimerase (
) (also known as RPE, pentose-5-phosphate 3-epimerase or PPE) is the enzyme that converts D-ribulose 5-phosphate (Ru5P) into D-xylulose 5-phosphate in Calvin's reductive pentose phosphate cycle. In Ralstonia eutropha (Alcaligenes eutrophus) two copies of the gene coding for PPE are known [
], one is chromosomally encoded , the other one is on a plasmid
. PPE has been found in a wide range of bacteria, archaebacteria, fungi and plants. All the proteins have from 209 to 241 amino acid residues. The enzyme has a TIM barrel structure.
This family also includes other enzymes from the ribulose-phosphate 3-epimerase family, like D-allulose-6-phosphate 3-epimerase and other putative pentose-5-phosphate 3-epimerases. D-allulose-6-phosphate 3-epimerase catalyses the reversible epimerization of D-allulose 6-phosphate to D-fructose 6-phosphate, but it can also catalyse with lower efficiency the reversible epimerization of D-ribulose 5-phosphate to D-xylulose 5-phosphate [
].
Glucose-6-phosphate dehydrogenase (
) (G6PDH) is a ubiquitous protein, present in bacteria and all eukaryotic cell types [
]. The enzyme catalyses the the first step in the pentose pathway, i.e. the conversion of glucose-6-phosphate to gluconolactone 6-phosphate in the presence of NADP, producing NADPH. The ubiquitous expression of the enzyme gives it a major role in the production of NADPH for the many NADPH-mediated reductive processes in all cells, and is critical for NADPH homeostasis and redox regulation []. Deficiency of G6PDH is a common genetic abnormality affecting millions of people worldwide. Many sequence variants, most caused by single point mutations, are known, exhibiting a wide variety of phenotypes with the distinctive one being chronic and drug- or food-induced hemolytic anemia, attributed to the inability to produce NADPH and withstand harmful oxidants in erythrocyte cells [,
].
The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described []. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.Glycosyltransferase family 31 (
) comprises enzymes with a number of known activities; N-acetyllactosaminide beta-1,3-N-acetylglucosaminyltransferase (
); beta-1,3-galactosyltransferase (
); fucose-specific beta-1,3-N-acetylglucosaminyltransferase (
); globotriosylceramide beta-1,3-GalNAc transferase (
) [
,
].
Rad1 is a component of the 9-1-1 cell-cycle checkpoint response complex, which plays a role in checkpoint activation that permits DNA-repair pathways to prevent cell cycle progression in response to DNA damage and replication stress [
,
]. The 9-1-1 complex is recruited to DNA lesions upon damage by the Rad17 (Rad24 in budding yeast)-replication factor C (RFC) clamp loader complex. The 9-1-1 complex is necessary for the recruitment of C12orf32/RHINO to sites of double-stranded breaks (DSB) occurring during the S phase []. Rad1 isoform 1 possesses 3'->5' double stranded DNA exonuclease activity [
].In Caenorhabditis elegans, the cell cycle checkpoint protein RAD1 homologue mrt-2 has a role in genome stability by promoting DNA double strand break-induced cell cycle arrest and apoptosis, and is required for maintaining telomere length and germline immortality [
,
,
].
The cryptochrome and photolyase families consist of structurally related flavin adenine dinucleotide (FAD) proteins that use the absorption of blue light to accomplish different tasks. The photolyasess use the blue light for light-driven electron transfer to repair UV-damaged DNA, while the cryptochromes are blue-light photoreceptors involved in the circadian clock for plants and animals [
,
]. On the basis of the primary structure, the cryptochrome/DNA photolyase family can be grouped into two classes []. The first class contains cryptochromes and DNA photolyases from eubacteria, archaea, fungi, animals and plants. The second class contains DNA photolyases from prokaryotes, plants and animals.This entry represents the class1 cryptochrome/DNA photolyase family. Its members include cryptochromes, DNA photolyases and cryptochrome-DASH (Cry-DASH). The Cry-DASH family members have been shown to act as photolyases with high degree of specificity for cyclobutane pyrimidine dimers in ssDNA [
].
Carbonic anhydrases (CA) are zinc-containing enzymes that catalyse the reversible hydration of carbon dioxide in a two-step mechanism, involving the nucleophilic attack of a zinc-bound hydroxide ion on carbon dioxide, followed by the regeneration of the active site by ionization of the zinc-bound water molecule and removal of a proton from the active site. They are ubiquitous enzymes involved in fundamental processes like photosynthesis, respiration, pH homeostasis and ion transport. There are three distinct groups of carbonic anhydrases - alpha, beta and gamma - which show no significant sequence identity or structural similarity [
,
,
,
].CAs are homotrimeric enzymes, with each subunit containing a left-handed parallel β-helix (LbH) structural domain, which is represented in this entry [
]. It is found at the N-terminal the cyanobacterial Carboxysome assembly protein CcmM, while the archaeal Carbonic anhydrase (CAH) only has this domain.
The transcription regulatory histone acetylation complex Spt-Ada-Gcn5 acetyltransferase (SAGA) is involved in RNA polymerase II-dependent transcriptional regulation of approximately 10% of yeast genes. SAGA preferentially acetylates histones H3 and H2B and deubiquitinates histone H2B []. SAGA is known as PCAF in vertebrates and PCAF acetylates nucleosomal histone H3 []. The SAGA complex consists of at least TRA1, CHD1, SPT7, TAF5, ADA3, SGF73, SPT20/ADA5, SPT8, TAF12, TAF6, HFI1/ADA1, UBP8, GCN5, ADA2, SPT3, SGF29, TAF10, TAF9, SGF11 and SUS1, and some of these components are present as two copies. The complex is built up from distinct modules, each of which has a separate function and crosslinks with either other proteins or other modules in the complex [].This entry includes transcriptional activator Spt7, which is a component of the transcription regulatory histone acetylation complexes SAGA, SLIK and SALSA [
,
,
].
The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids [
,
].The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
This entry represents a conserved site in the beta subunit that includes the histidine residues thought to be involved in bacteriochlorophyll binding.
The antenna complexes of photosynthetic bacteria function as light-harvesting systems that absorb light and transfer the excitation energy to the reaction centres. The antenna complexes usually comprise 2 polypeptides (alpha- and beta-chains), 2-3 bacteriochlorophyll molecules and some carotenoids [
,
].The alpha- and beta-chains are small proteins of 40-70 residues. Each has an N-terminal hydrophilic cytoplasmic domain, a single transmembrane (TM) region, and a small C-terminal hydrophilic periplasmic domain. In both chains, the TM domain houses a conserved His residue, presumed to be involved in binding the magnesium atom of a bacteriochlorophyll group. The beta-chains are characterised by a further histidine at the C-terminal extremity of the cytoplasmic domain, which is also thought to be involved in bacteriochlorophyll binding.
This superfamily represents the structural domain of the beta subunit, encapsulating the N-terminal, TM and C-terminal domains.
The polo-like Ser/Thr kinases (Plk1, Plk2/Snk, Plk3/Prk/Fnk, Plk4/Sak, and the inactive kinase Plk5) play various roles in cytokinesis and mitosis. At their C terminus, they contain a tandemly repeated polo-box domain (PBD) (in the case of Plk4, a tandem repeat of cryptic PBDs is found in the middle of the protein followed by a C-terminal single repeat), which appears to be involved in autoinhibition and in mediating the subcellular localization. The latter may be controlled via interactions between the polo-box domain and phospho-peptide motifs. The phosphopeptide binding site is formed at the interface between the two tandemly repeated PBDs. The PBDs of Plk4/Sak appear unique in participating in homodimer interactions, though it is not clear whether and how they interact with phosphopeptides [
,
,
,
,
,
].This entry represents the first (cryptic) polo-box domain of Plk4.
Porins form aqueous channels for the diffusion of small hydrophillic molecules across the outer membrane [
]. Individual 16-strand anti-parallel β-barrels form a central pore, and trimerizes through mainly hydrophobic interactions at the interface. Trimers are stabilized by hytrophillic clamping of Loop L2. Loop 3 bends into the pore, creating an elliptical constriction of about 7 x 11 angstroms, large enough to allow passage of a glucose molecule without steric hindrance. Removal of the C-terminal residue (usually Phe) destabilizes the trimer and removal of the 16th β-sheet abolishes trimerization. Unlike typical membrane proteins, porins lack long hydrophobic stretches. Short turns are found at the smooth, periplasmic end, longer irregular loops are found at the rough, extracellular end. The C-terminal residue forms a salt bridge with the N terminus [].This entry represents the structural domain found in Gram-negative bacterial porins.
This entry represents a domain found at the C-terminal end of Pyrimidine/purine nucleotide 5'-monophosphate nucleosidase from Escherichia coli (PpnN, also known as YgdH) and similar proteins mainly found in gammaproteobacteria. PpnN is a nucleosidase that catalyses the hydrolysis of the N-glycosidic bond of diverse pyrimidine and purine nucleotide 5'-monophosphates to form ribose 5-phosphate and the corresponding free base. It can use AMP, GMP, IMP, CMP, dTMP and UMP as substrates. This enzyme adopts a tetrameric configuration with allosteric (p)ppGpp binding sites located between subunits. The binding of this alarmone molecule, which play a role in the bacterial stringent response, gives rise to a large conformational change involving the terminal region that leads to the exposure of the catalytic pocket. The C-terminal domain shows a completely α-helical fold with an extension that wraps around the central domain [
,
].
The nitrate reductase enzyme complex allows bacteria to use nitrate as an electron acceptor during anaerobic growth. The enzyme complex consists of a tetramer that has an alpha, beta and 2 gamma subunits. The alpha and beta subunits have catalytic activity and the gamma subunits attach the enzyme to the membrane and are b-type cytochromes that receive electrons from the quinone pool and transfers them to the beta subunit. The sequences in this family are the beta subunit for nitrate reductase I (narH) and nitrate reductase II (narY) for Gram-positive and Gram-negative bacteria. A few thermophiles and archaea also match the model. A number of the sequences in this set are experimentally characterised, these include: E.Coli NarH (
) and NarY (
) [
,
], from Bacillus subtilis, and related proteins from Pseudomonas fluorescens, Paracoccus denitrificans, and Paracoccus halodenitrificans (Halomonas halodenitrificans).
This subset of the radical-SAM domain includes a number of probable activating proteins acting on different enzymes all requiring an amino-acid-centred radical. The closest relatives to this family are the pyruvate-formate lyase activating enzyme (PflA,
,
) and the anaerobic ribonucleotide reductase activating enzyme (
). Included within this subfamily are activators of hydroxyphenyl acetate decarboxylase (HdpA, [
]), benzylsuccinate synthase (BssD, []), gycerol dehydratase (DhaB2, []), trans-4-hydroxy-L-proline dehydratase (pflE, []) as well as enzymes annotated in Escherichia coli as activators of different isozymes of pyruvate-formate lyase (PFLC and PFLE) however, these appear to lack characterisation and may activate enzymes with distinctive functions. Most of the sequence-level variability between these forms is concentrated within an N-terminal domain, which follows a conserved group of three cysteines and contains a variable pattern of 0 to 8 additional cysteines.
The independent cloning of rodent EBF/Olf-1 and Drosophila melanogaster Collier has defined
a family of transcription factors, the Collier or COE family []. COE proteinshave various functions in different organisms.
In mouse, COE1 has a role in B-cell differentiation, and could also perform a
role in neuronal differentiation. All three COE are expressed in immatureolfactory neuronal precursors and mature olfactory neurons as well as in
developping nervous system during embryogenesis.In Drosophila, Collier is involved in the formation of the embryonic somatic
muscle DA3, in the patterning of the wing by mediating Hedgehog activity.It could also act as a second-level regulator in the patterning of embryonic
head. This conserved region is located in a domain thought to be part of the DNA-binding region. The signature includes four conserved cysteines that could be part of a zinc-finger motif.
Corticotropin-releasing factor (CRF) (corticoliberin) [
] is a hormone from the hypothalamus that regulates the release of corticotropin (ACTH) from the pituitary gland. CRF is evolutionary related to a number of other active peptides which are listed below.Urocortin (Ucn) [
], a brain mammalian peptide with corticotropin-releasing factor activity.Urotensin 1 from the urophysis of fish. Like CRF and Ucn, it acts in ACTH secretion.Sauvagine from frog skin, a peptide with a potent hypotensive action that elicits a diuretic effect.Diuretic hormone (DH) (or diuretic peptide (DP) from a variety of insects. DH is involved in the regulation of fluid secretion [
].All these hormones are peptides of about 40 amino acid residues which are C-terminally amidated and processed from a larger precursor protein. This signature is a pattern of conserved residues, running from position 4 to 19 in these peptides.
The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded non structural proteins (NSP) plays a vital role during initial and intermediate phases of the viral life cycle. NSP15 forms a hexamer made of dimers of trimers which is suggested to be a functional unit, responsible for the endoribonuclease activity. The NSP15 monomer consists of three domains: N-terminal, middle and C-terminal [
,
]. The catalytic function of NSP15 resides in the C-terminal NendoU domain. The active site carries six key residues conserved among SARS-CoV-2, SARS-CoV and MERS-CoV, suggesting that its activity is important for sustained replication in the host [,
].This entry represents the N-terminal oligomerization domain of the NSP15, which stabilises the hexamer and is critical for its formation [
]. This domain is composed of three-stranded antiparallel β-sheet and two α-helices [,
,
,
].
Lysozymes are ancient and important components of the innate immune system of animals that hydrolyse peptidoglycan, the major bacterial cell wall polymer. Various mechanisms have evolved by which bacteria can evade this bactericidal enzyme, one being the production of lysozyme inhibitors. MliC (membrane bound lysozyme inhibitor of c-type lysozyme) of E. coli and Pseudomonas aeruginosa, possess lysozyme inhibitory activity and confer increased lysozyme tolerance upon expression in E. coli [
]. Structural analyses show that the invariant loop of MliC plays a crucial role in the inhibition of the lysozyme by its insertion into the active site cleft of the lysozyme, where the loop forms hydrogen and ionic bonds with the catalytic residues [].Interestingly, lipoprotein LprI has a C-terminal MliC domain, and has
been identified only in virulence-associated mycobacterial strains, where it acts as a lysozyme inhibitor [].
Calcipressins (RCANs) are a novel family of calcineurin regulators that have been suggested as key factors contributing to Down syndrome in humans. Three human calcipressins have been identified, calcipressin 1-3. Calcipressin 1 is also known as modulatory calcineurin-interacting protein 1 (MCIP1), Adapt78 and Down syndrome critical region 1 (DSCR1). Calcipressin 2 is variously known as MCIP2, ZAKI-4 and DSCR1-like 1. Calcipressin 3 is also called MCIP3 and DSCR1-like 2 [
]. Calcipressins contain an N-terminal RNA recognition motif (RRM), a highly conserved SP repeat domain containing the phosphorylation site by GSK-3, a well-known PxIxIT motif responsible for docking many substrates to calcineurin, and a C-terminal TxxP motif [].Calcineurin is a calcium-responsive enzyme that dephosphorylates the nuclear factor of activated T cells (NFAT). In doing so, it promotes its nuclear translocation and uniquely links calcium signalling to transcriptional regulation [].
The transforming growth factors-beta constitute a family of
multi-functional cytokines that regulate cell growth and differentiation []. Many cells synthesise TGF-beta, and essentially all have specific receptors for this peptide []. TGF-beta regulates the actions of many other peptide growth factors and determines a positive or negative direction of their effects. The protein functions as a disulphide-linked homodimer. Its sequence is characterised by the presence of several C-terminal cysteine residues, which form interlocking disulphide links arranged in a knot-like topology. A similar "cystine-knot"arrangement has been noted in the structures of some enzyme inhibitors and neurotoxins that bind to voltage-gated Ca2+ channels, although the precise topology differs.The three-dimensional structures of several members of the TGF-beta
super-family have been deduced [,
,
]. TGF-beta genes are expressed differentially, suggesting that the various TGF-beta species may have distinct physiological roles
in vivo.
This is C-terminal domain (CTD) of M60-peptidases [
]. It can also be found at the C-terminal region of gingipain B (RgpB) from P. gingivalis. It was found to possess a typical Ig-like fold encompassing seven antiparallel β-strands organized in two β-sheets, packed into a β-sandwich structure that can spontaneously dimerise through C-terminal strand swapping. Translocation of gingipains from the periplasm across the OM is dependent on the conserved CTD, which appears to be important for secretion of the proteins and in particular, truncation of the last few C-terminal residues of this domain leads to accumulation of gingipains in the periplasm. Subsequently, the T9SS targeting signal was demonstrated to reside within the last 22 residues at the C terminus of the CTD. During gingipain translocation across the OM, the CTD is cleaved off by PorU [].
The ~150-amino acid PA14 domain, named after its location in the protective
antigen of anthrax toxin, is found in a variety of bacterial and eukaryoticproteins such as glycosidases, glycosyltransferases, proteases, amidases,
toxins, adhesins and signaling molecules. The PA14 domain is combined in amosaic manner with various catalytic or non-catalytic domains directly or
indirectly implicated in binding carbohydrate or peptidoglycan. It could be acarbohydrate-binding module [
,
,
].The PA14 domain is a β-barrel structure comprising two β-sheets. The N and C termini of the domain are close together in space,
presumably, thereby facilitating the insertion of the PA14 domain into otherrecognized domains without structural disruption [
,
,
].This entry also recognizes the related GLEYA domain (
), which is a carbohydrate-binding domain found in fungal adhesins (also referred to as agglutinins or flocculins) [
].
The bacterial flagellar motor is a rotary motor complex composed of various proteins. MotX and MotY are essential for the Na+-driven flagellar motor motility of Vibrio, Shewanella and Aeromonas species. MotY is main component for T-ring formation and absence of MotY completely disrupt the T-ring formation [
]. This is the N-terminal domain of MotY which is shown to be essential for motility and responsible for the interaction with both MotX and the basal body. Functional analysis suggests that MotY-N connects the basal body to MotX and that the PomA/PomB complex associates with MotX to form the functional stator complex around the rotor. MotY-N alone does not associate strongly with the basal body, but the partial T-ring structure made of the MotY-N/MotX complex is sufficient to allow at least a few PomA/PomB stator complexes to be incorporated into the motor [].
This family contains methyltransferases from bacteria and fungi, including VrtF, AdaD, CtvB and VerB. The gene encoding O-methyltransferase VrtF is part of the gene cluster that mediates the biosynthesis of viridicatumtoxin, a tetracycline-like fungal polyketide [
]. Similarly, the ctvB gene is part of a cluster that encode proteins for the biosynthesis of citreoviridin, an inhibitor of the F1-ATPase beta-subunit. CtvB methylates the alpha-pyrone hydroxyl group of an intermediate to generate citreomontanin []. Methyltransferase VerB is encoded by of the gene cluster that mediates the biosynthesis of the neurotoxin verrucosidin, a methylated alpha-pyrone polyketide that inhibits oxidative phosphorylation in mitochondria and thereby causes neurological diseases []. The adaD gene is part of the gene cluster that mediates the biosynthesis of the linear tetracyclic TAN-1612 neuropeptide Y receptor antagonist. AdaD is O-methyltransferase involved in Secondary metabolite biosynthesis [].
Nicotinate phosphoribosyltransferase (
) is the rate-limiting enzyme that catalyses the first reaction in the NAD salvage synthesis [
]. Members in this family can be split into two further subfamilies represented in and
. Members in
have a different (longer) spacing of several key motifs and have an additional C-terminal domain of up to 100 residues. However, one argument suggesting that this family represents the same enzyme is that no species has a member of both subfamilies. Another is that the gene encoding this protein is located near other NAD salvage biosynthesis genes in Nostoc and in at least four different Gram-positive bacteria.
Nicotinamide phosphoribosyl transferase (NAMPT) catalyses the condensation of nicotinamide with 5-phosphoribosyl-1-pyrophosphate to yield nicotinamide mononucleotide, an intermediate in the biosynthesis of NAD [
,
]. NAMPT is also known as pre-B cell colony-enhancing factor (PBEF) or visfatin.
This entry represents the adenylate kinase 2 (AK2) subfamily of the adenylate kinases (AKs), which are nucleoside monophosphate kinases that catalyse the phosphorylation of AMP by using ATP or GTP as phosphate donors. Proteins in this entry include AK2 from humans, Adk1 from budding yeasts. In humans, nine different AK isoenzymes have been identified (AK1-9). AK2 is the major mitochondrial isoform and is expressed in the mitochondrial intermembrane space of tissues rich in mitochondria such as liver, heart and skeletal muscle [
]. Mutations in AK2 gene cause the reticular dysgenesis (aleukocytosis), which is the most severe form of inborn severe combined immunodeficiencies []. In budding yeasts, Adk1 (also known as Aky2) is the major isoform of AKs. It is found in both cytoplasm and mitochondrial intermembrane space. It has no cleavable mitochondrial targeting sequence [
].
This entry represents the forkhead associated (FHA) domain found at the N-terminal end of Aprataxin. The FHA domain is a small phosphopeptide recognition module. Aprataxin (
/
) is a DNA-binding protein involved in single-strand DNA break repair, double-strand DNA break repair, and base excision repair [
,
]. It catalyses the release of adenylate groups covalently linked to 5'-phosphate termini, resulting in the production of 5'-phosphate termini that can be efficiently rejoined. It can also hydrolyse adenosine 5'-monophosphoramidate (AMP-NH(2)) and diadenosine tetraphosphate (AppppA), but with lower catalytic activity. Likewise, it catalyses the release of 3'-linked guanosine (DNAppG) and inosine (DNAppI) from DNA but has higher specific activity with 5'-linked adenosine (AppDNA) [,
,
,
,
,
,
]. Mutations in the gene APTX have been associated with ataxia-ocular apraxia and with coenzyme 10 deficiency [,
,
].
This entry reprsents the GTP-binding domain found in peptide chain release factor 3. Peptide chain release factor 3 (RF3) is a protein involved in the termination step of translation in bacteria. Termination occurs when class I release factors (RF1 or RF2) recognize the stop codon at the A-site of the ribosome and activate the release of the nascent polypeptide. The class II release factor RF3 then initiates the release of the class I RF from the ribosome. RF3 binds to the RF/ribosome complex in the inactive (GDP-bound) state. GDP/GTP exchange occurs, followed by the release of the class I RF. Subsequent hydrolysis of GTP to GDP triggers the release of RF3 from the ribosome. RF3 also enhances the efficiency of class I RFs at less preferred stop codons and at stop codons in weak contexts [
,
].
The precise function of this protein is unknown. However, it is thought that this entry represents the gasdermin family which plays a role as a secretory or metabolic product involved in the secretory pathway and includes gasdermins A-E (GSDMA-E). A N-terminal fragment released by proteolysis of gasmerdin A binds to lipids and homo-oligomerizes in the membrane forming pores, which may have a bactericidal function [
].GSDMB (GSDM) may play a role in achieving and maintaining the final differentiation state of epithelial cells [
,
]. A deletion/insertion mutation in GSDMB (DFNA5) is associated with an autosomal dominant non-syndromic hearing impairment form [].Certain gasdermins are cleaved by inflammatory and apoptotic caspases [
]. Gasmedin E is cleaved by caspase-3 and the N-terminal fragment released forms pores in the cell membrane, switching from cell death by apoptosis to pyroptosis [].
The RegB endoribonuclease encoded by Bacteriophage T4 is a unique sequence-specific nuclease that cleaves in the middle of GGAG or, in a few cases, GGAU tetranucleotides, preferentially those found in the Shine-Dalgarno regions of early phage mRNAs. T4 regB expression is regulated autogenously by attacking its own mRNA. The deduced primary structure of RegB proteins in many phages is almost identical to that of T4, while the sequences of RegB encoded by Enterobacteria phage RB69, Enterobacteria phage TuIa and Enterobacteria phage RB49 show substantial divergence from their T4 counterpart [
]. In RB49 regB expression is regulated by both RegB and Escherichia coli endoribonuclease E. It's worth noting that this family does not fall into the Lysozyme-like family, but rather is a new member of the RelE/YoeB structural and functional family of ribonucleases specialising in mRNA inactivation within the ribosome [
].
Myticin is a cysteine-rich peptide produced in three isoforms, A, B and C, by Mytilus galloprovincialis (Mediterranean mussel). Isoforms A and B show antibacterial activity against Gram-positive bacteria, while isoform B is additionally active against the fungus Fusarium oxysporum and a Gram-negative bacterium, Escherichia coli (streptomycin resistant strain D31) []. Myticin-prepro is the precursor peptide. The mature molecule, named myticin, consists of 40 residues, with four intramolecular disulphide bridges and a cysteine array in the primary structure different from that of previously characterised cysteine-rich antimicrobial peptides. The first 20 amino acids are a putative signal peptide, and the antimicrobial peptide sequence is a 36-residue C-terminal extension. Such a structure suggests that myticins are synthesised as prepro-proteins that are then processed by various proteolytic events before storage in the haemocytes as the active peptide. Myticin precursors are expressed mainly in the haemocytes.
This entry represents the SET domain found in KMT2E.The protein known as histone-lysine N-methyltransferase 2E (KMT2E, mixed-lineage leukemia 5 or MLL5) has been shown to lack key residues and an essential loop in the the SET-I subdomain required for binding substrate and cofactors [
]. MLL5 had been thought to be specific for mono- and dimethylation of 'Lys-4' of histone H3 (H3K4me1 and H3K4me2; which are specific tags for epigenetic transcriptional activation), and a component of an MLL5 complex, but the paper describing this alleged complex has been retracted by the authors []. MLL5 mediates hematopoietic cell homeostasis, spermatogenesis, cell cycle progression, and survival [,
]. It is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3 []. Overexpression of the MLL5 gene induced cell cycle arrest in G(1) phase [].
