Members of this family are responsible for binding the DNA attachment sites at each end of the Mu genome. They adopt a secondary structure comprising a four helix bundle tightly packed around a hydrophobic core consisting of aliphatic and aromatic amino acid residues. Helices 1 and 2 are oriented antiparallel to each other. Helix 3 crosses helices 1 and 2 at angles of 60 and 120 degrees, respectively. Excluding the C-terminal helix 4, the fold of the I-gamma subdomain is remarkably similar to that of the homeodomain family of helix-turn-helix DNA-binding proteins, although their amino acid sequences are completely unrelated [1].
This is a family of bacterial 3TM holins. In Rhodobacter capsulatus the protein is expressed just overlapping and downstream of a putative N-acetylmuramidase lysozyme (an endolysin) thought to be responsible for lysing a phage particle, RcGTA - a gene-transfer agent. A holin would be necessary for such an endolysin to access the peptidoglycan [1]. Gene-transfer agents are bacteriophage-like genetic elements with the sole known function of horizontal gene transfer, serving an important role in microbial evolution. In order to be released from the cell these require the combined action of an endolysin and this holin [2].
Urea carboxylase (UC) catalyses a two-step, ATP- and biotin-dependent carboxylation reaction of urea. It is composed of biotin carboxylase (BC), carboxyltransferase (CT), and biotin carboxyl carrier protein (BCCP) domains. The CT domain of UC consists of four subdomains, named A, B, C and D. This domain covers the A and B subdomains of the CT domain. This domain covers the whole length of KipA (kinase A) from Bacillus subtilis [1]. It can also be found in S. cerevisiae urea amidolyase Dur1,2, which is a multifunctional biotin-dependent enzyme with domains for urea carboxylase and allophanate (urea carboxylate) hydrolase activity[2].
Urea carboxylase (UC) catalyses a two-step, ATP- and biotin-dependent carboxylation reaction of urea. It is composed of biotin carboxylase (BC), carboxyltransferase (CT), and biotin carboxyl carrier protein (BCCP) domains. The CT domain of UC consists of four subdomains, named A, B, C and D. This domain covers the C and D subdomains of the CT domain. This domain covers the whole length of kipI (kinase A inhibitor) from Bacillus subtilis [1]. It can also be found in S. cerevisiae urea amidolyase Dur1,2, which is a multifunctional biotin-dependent enzyme with domains for urea carboxylase and allophanate (urea carboxylate) hydrolase activity[2].
Cache_3 is the periplasmic sensor domains of sensor histidine kinase of E. coli DcuS. This domain forms one of the components of the two-component signalling system that allows bacteria to adapt to changing environments. The ability of bacteria to monitor and adapt to their environment is crucial to their survival, and two-component signal transduction systems mediate most of these adaptive responses. One component is a histidine kinase sensor - this domain - most commonly part of a homodimeric transmembrane sensor protein, and the second component is a cytoplasmic response regulator. The two components interact in tandem through a phospho-transfer cascade [1].
The members of this family are enzymes that cleave peptides. These proteases require zinc for catalysis. Members of this family contain two conserved disulphide bridges, these are joined 1-4 and 2-3. Members of this family have an amino terminal propeptide which is cleaved to give the active protease domain. All other linked domains are found to the carboxyl terminus of this domain. This family includes: Astacin Swiss:P07584, a digestive enzyme from Crayfish. Meprin, Swiss:Q16819, a multiple domain membrane component that is constructed from a homologous alpha and beta chain. Proteins involved in morphogenesis such as Swiss:P13497, and Tolloid from drosophila Swiss:P25723.
TAtT is a family of one component, the T-component, of a sub-set of TRAP-Ts or Tripartite ATP-independent periplasmic transporters. TRAP-Ts are bacterial transport systems implicated in the import of small molecules into the cytoplasm in bacteria. They are all periplasmic lipoproteins. TatT consists of a 13-alpha-helical fold containing cryptic tetratricopeptide repeat motifs (cTPRs) and encompassing a pore, ie is a water-soluble trimer whose protomers are each perforated by a pore. It forms a complex with a P component, and a putative ligand-binding cleft of TatPT aligns with the pore of TatT [1]. Family TatPT is represented by some members of Pfam:PF03480.
CPG4 is a domain family found in nematodes of one of nine core chondroitin proteoglycans. Vertebrates produce multiple chondroitin sulfate proteoglycans that play important roles in development and tissue mechanics. In the nematode Caenorhabditis elegans, the chondroitin chains lack sulfate but nevertheless play essential roles in embryonic development and vulval morphogenesis. CPG4 has the largest predicted mass of the C. elegans CPGs at 84 kDa. The majority of its 35 predicted glycosaminoglycan attachment sites reside in the COOH-terminal half of the protein, of which four sites were confirmed by DTT modification [1]. The family is rich in conserved cysteines.
This family of serine peptidases belong to MEROPS peptidase family S13 (D-Ala-D-Ala carboxypeptidase C, clan SE). The active site residues occur in the motif SXXK. D-Ala-D-Ala carboxypeptidase C is involved in the metabolism of cell components [1,2]. There are three families of serine-type D-Ala-D-Ala peptidase (designated S11, S12 and S13), which are also known as low molecular weight penicillin-binding proteins. Family S13 comprises D-Ala-D-Ala peptidases that have sufficient sequence similarity around their active sites to assume a distant evolutionary relationship to other clan members; members of the S13 family also bind penicillin and have D-amino-peptidase activity [3,4].
SPRR genes (formerly SPR) encode a novel class of polypeptides (small proline rich proteins) that are strongly induced during differentiation of human epidermal keratinocytes in vitro and in vivo. The most characteristic feature of the SPRR gene family resides in the structure of the central segments of the encoded polypeptides that are built up from tandemly repeated units of either eight (SPRR1 and SPRR3) or nine (SPRR2) amino acids with the general consensus XKXPEPXX where X is any amino acid [1]. In order to avoid bacterial contamination due to the high polar-nature of the HMM the threshold has been set very high.
This domain is found in phage proteins, such as A0A2H5BHG5 from Acinetobacter phage SH-Ab 15497, which are associated with PurZ, an enzyme that catalyses the synthesis of diaminopurine (Z), a DNA modification that gives phages an advantage for evading host restriction enzymes activity [1]. This domain has dATP and dGTP pyrophosphohydrolase activity; it catalyses the hydrolysis of dATP/dGTP to pyrophosphate and dAMP/dGMP, respectively, with little or no activities for NTPs and pyrimidine dNTPs. It is suggested that enzymes containing this domain supply dGMP as the substrate for PurZ, elevating dZTP level to promote Z incorporation [1].
This family includes members such as BLF1 (Burkholderia lethal factor 1) also known as BPSL1549. BLF1 is a potent toxin from Burkholderia pseudomallei causing melioidosis. BLF1 interacts with the human translation factor eIF4A causing deamidation of Gln339 to Glu. Thereby, reducing endogenous host cell protein synthesis and triggering increased stress granule formation, which is associated with translational blocks. Structural analysis of BLF1 revealed an alpha/beta fold comprising a sandwich of two mixed beta-sheets surrounded by loops and alpha-helices, where the beta-sheet core of the catalytic pocket is structurally similar to that of the deamidase domain of CNF1 Pfam:PF05785 [1].
The wheel domain is found at the C-terminus of yeast Cns1 and human TTC4 proteins [1]. The structure of the domain shows an overall fold consisting of a twisted five-stranded beta sheet surrounded by several alpha helices [1]. The Hsp90 chaperone machinery in eukaryotes comprises a number of distinct accessory factors. Cns1 is one of the few essential co-chaperones in yeast. Cns1 is important for maintaining translation elongation, specifically chaperoning the elongation factor eEF2 [1]. In this context, Cns1 interacts with the novel co-factor Hgh1 and forms a quaternary complex together with eEF2 and Hsp90 [1].
This is the N-terminal CBM-like domain in exo-beta-agarase proteins (EC:3.2.1.81) found in the marine microbe Saccharophagus degradans. This enzyme catalyzes a critical step in the metabolism of agarose by S. degradans through cleaving agarose oligomers into neoagarobiose products that can be further processed into monomers. The CBM-like domain is structurally very similar to some CBM families. A loop in the CBM-like domain is involved in forming the roof of the active site channel. The contribution of the CBM-like domain to formation of the active site of the enzyme supports a role in substrate recognition explaining the exo-mode of beta-agarase action [1].
GramPos_pilinBB is one of the major backbone units of Gram-positive pili, such as those from S.pneumoniae [1]. There are three major pilin subunits that form the polymeric backbone of the pilin from S. pneumoniae, constructed of three transthyretin-like, CnaB, domains along with a crucial N-terminal domain, D1. The three Cna-B like domains are stabilised by internal Lys-Asn isopeptdie bonds, Gram-positive pili are formed from a single chain of covalently linked subunit proteins (pilins), usually comprising an adhesin at the distal tip, a major pilin that forms the polymer shaft and a minor pilin that mediates cell wall anchoring at the base [2].
GramPos_pilinD3 is one of the major backbone units of Gram-positive pili, such as those from S.pneumoniae [1]. There are three major pilin subunits that form the polymeric backbone of the pilin from S. pneumoniae, constructed of three transthyretin-like, CnaB, domains along with a crucial N-terminal domain, D1. The three Cna-B like domains are stabilised by internal Lys-Asn isopeptdie bonds, Gram-positive pili are formed from a single chain of covalently linked subunit proteins (pilins), usually comprising an adhesin at the distal tip, a major pilin that forms the polymer shaft and a minor pilin that mediates cell wall anchoring at the base [2].
Staphylococcal Cassette Chromosome, or SCC elements, are a family of genomic islands found in S. aureus and closely related species. SCC elements that carry the mecA gene are called SCCmec and render S. aureus methicillin-resistant, creating the MRSA strains. Cch, the self-loading helicase encoded by SCCmec type IV, belongs to the pre-sensor II insert clade of AAA+ ATPases, as do the archaeal and eukaryotic MCM-family replicative helicases. The N-terminal domain carries Pfam:PF06048. The central domain (residues 157-438) contains an AAA+ ATPase fold. This domain is found at the C-terminal region, it is a winged helix-turn-helix (WH) domain typical of many dsDNA-binding proteins [1].
This is a family of unknown function found in Chordata. This domain is located downstream the N-terminal of Fip1 Pfam:PF05182. Family members such as Swiss:P70537 and Swiss:P70675 contain this domain. The Tsx gene resides at the X-inactivation centre and once thought to encode a protein expressed in testis. However, this was disputed upon further analysis. ORF and immunostaining analysis concluded that Tsx may be non-coding. Tsx long transcript is abundantly expressed in meiotic germ cells, embryonic stem cells, and brain. In vertebrates, Fip1 is the evolutionary precursor of eutherian Tsx, hence its location upstream from the Tsx gene [1].
This family features glycosyltransferases belonging to glycosyltransferase family 52 [1], which have alpha-2,3- sialyltransferase (EC:4.2.99.4) and alpha-glucosyltransferase (EC 2.4.1.-) activity. For example, beta-galactoside alpha-2,3- sialyltransferase expressed by Neisseria meningitidis (Swiss:P72097) is a member of this family and is involved in a step of lipooligosaccharide biosynthesis requiring sialic acid transfer; these lipooligosaccharides are thought to be important in the process of pathogenesis [2]. This family includes several bacterial lipooligosaccharide sialyltransferases similar to the Haemophilus ducreyi LST protein. Haemophilus ducreyi is the cause of the sexually transmitted disease chancroid and produces a lipooligosaccharide (LOS) containing a terminal sialyl N-acetyllactosamine trisaccharide [3].
The J-binding protein 1 (JBP1) is essential for biosynthesis and maintenance of DNA base-J (beta-d-glucosyl-hydroxymethyluracil). Base-J and JBP1 are confined to some pathogenic protozoa and are absent from higher eukaryotes, prokaryotes and viruses. JBP1 recognizes J-containing DNA (J-DNA) through the DNA-Binding JBP1 domain (DB-JBP1), which binds to J-DNA with approximately the same affinity and specificity as full-length JBP1. Structure analysis of DB-JBP1 revealed a helix-turn-helix variant fold, a 'helical bouquet' with a 'ribbon' helix encompassing the amino acids responsible for DNA binding. Mutation of a single residue (Asp525) in the ribbon helix abrogates specificity toward J-DNA [1].
The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. NPCs are formed by multiple copies of 34 distinct proteins, termed nucleoporins (nups). In yeast, the channel nups Nsp1, Nup49, and Nup57 constitute part of the central transport channel and form the diffusion barrier with their disordered phenylalanine-glycine (FG) repeats. Structural studies of yeast Nup57 indicate that it contains left-handed coiled-coil domains (CCD1-3). This entry represents the third CCD located at the C-terminal region of Nup57 which is composed of five heptad repeats. Nup57 in yeast is the equivalent to human Nup54 Pfam:PF13874 [1].
The crystal structure of hydrazine synthase multiprotein complex isolated from the anammox organism Kuenenia stuttgartiensis implies a two-step mechanism for hydrazine synthesis: a three-electron reduction of nitric oxide to hydroxylamine at the active site of the gamma-subunit and its subsequent condensation with ammonia, yielding hydrazine in the active centre of the alpha-subunit. The alpha-subunit consists of three domains: an N-terminal domain which includes a six-bladed beta-propeller, a middle domain binding a pentacoordinated c-type haem (haem alphaI) and a C-terminal domain which harbours a bis-histidine-coordinated c-type haem (haem alphaII). This entry represents the middle domain of subunit alpha of hydrazine synthase (HZS) [1].
This family consists of the lactophorin precursors proteose peptone component 3 (PP3) and glycosylation-dependent cell adhesion molecule 1 (GlyCAM-1). GlyCAM-1 functions as a ligand for L-selectin, a saccharide-binding protein on the surface of circulating leukocytes, and mediates the trafficking of blood-born lymphocytes into secondary lymph nodes. In this context, sulphatation of the carbohydrates of GlyCAM-1 has been shown to be a critical structural requirement to be recognised by L-selectin. GlyCAM-1 is also expressed in pregnant and lactating mammary glands of mouse and in an unknown site in the lung, in the bovine uterus and rat cochlea [1].
In citrate-utilising prokaryotes, citrate lyase EC:4.1.3.6 cleaves intracellular citrate into acetate and oxaloacetate, and is organised as a functional complex consisting of alpha, beta, and gamma subunits. The gamma subunit serves as an acyl carrier protein (ACP), and has a 2'-(5''-phosphoribosyl)-3'-dephospho-CoA prosthetic group. The citrate lyase is active only if this prosthetic group is acetylated; this acetylation is catalysed by an acetate:SH-citrate lyase ligase. The alpha subunit substitutes citryl for the acetyl group to form citryl-S-ACP. The beta subunit completes the reaction by cleaving the citryl to yield oxaloacetate and (regenerated) acetyl-S-ACP. This family represents the alpha subunit EC:2.8.3.10.
The minichromosome maintenance (Mcm) complex is the replicative helicase in eukaryotic species, that plays essential roles in the initiation and elongation phases of DNA replication. During late M and early G(1), the Mcm complex is loaded onto chromatin to form prereplicative complex in a Cdt1-dependent manner. This entry represents the C-terminal domain of human Mcm6 which is the Cdt1 binding domain (CBD). The structure of CBD exhibits a typical winged helix fold that is generally involved in protein-nucleic acid interaction. The CBD failed to interact with DNA in experiments [1]. The CBD-Cdt1 interaction involves the helix-turn-helix motif of CBD [1].
Apc1 is the largest of the subunits of the anaphase-promoting complex or cyclosome. The anaphase-promoting complex is a multiprotein subunit E3 ubiquitin ligase complex that controls segregation of chromosomes and exit from mitosis in eukaryotes. Apc1 consists of a N-terminal WD40 beta-propeller domain, followed by the middle domain (Mid-N), a PC domain and the C-terminal domain (MidC). This entry represents the middle domain of Apc1, MidN (also referred to as the first helical domain), that coaleses with the C-terminal domain to form Apc1Mid that connects Apc1WD40 with Apc1PC [1,2]. Apc1Mid consists of an alpha-solenoid capped by a beta-sandwich [2].
This family represents the C terminal kinase domain of Hpr Serine/threonine kinase PtsK. This kinase is the sensor in a multicomponent phosphorelay system in control of carbon catabolic repression in bacteria [1]. This kinase in unusual in that it recognises the tertiary structure of its target and is a member of a novel family unrelated to any previously described protein phosphorylating enzymes [1]. X-ray analysis of the full-length crystalline enzyme from Staphylococcus xylosus at a resolution of 1.95 A shows the enzyme to consist of two clearly separated domains that are assembled in a hexameric structure resembling a three-bladed propeller [2].
This Polo box (PB) domain is found in Polo-like kinase 4 (Plk4) present in Drosophila melanogaster. Plk4 is a conserved component in the duplication pathway of centrioles which is needed to prevent chromosomal instability. Plk4 localizes to centrioles in M/G1. Structural analysis reveals two tandem, homodimerized polo boxes, PB1-PB2, that form a winged architecture. This domain is PB2, together with PB1 Pfam:PF18190 , they are required for binding the centriolar protein Asterless (Asl) as well as robust centriole targeting. In other words, PB1-PB2 cassette collectively binds Asl and affords robust centriole localization, optimally positioning the kinase domain for trans-autophosphorylation [1].
Cue1p (coupling of ubiquitin conjugation to ER degradation protein 1) is an integral component of yeast endoplasmic reticulum (ER)-associated degradation (ERAD) ubiquitin ligase (E3) complexes. It tethers the ERAD ubiquitin-conjugating enzyme (E2), Ubc7p, to the ER and prevents its degradation, and also activates Ubc7p. This domain represents the Ubc7p-binding region (U7BR) of Cue1p with Ubc7p. The U7BR is as E2-binding domain that includes three alpha-helices that interact extensively with the 'backside' of Ubc7p. U7BR stimulates both RING-independent and RING-dependent ubiquitin transfer from Ubc7p. Moreover, the U7BR enhances ubiquitin-activating enzyme (E1)-mediated charging of Ubc7p with ubiquitin [1].
This is a eukaryotic/eumetazoan PIN like domain found in the C-terminal region of bilateral ZNF451 proteins such as isoform 1 of human ZNF451. ZNF451 was shown to interact with p300 by the PIN-like domain and to negatively regulate TGF-beta signalling in a p300-dependent and sumoylation-independent manner. This domain is suggested to posses a potential active nuclease due to the presence of at least four conserved Asp residues in the predicted active site. Furthermore, it contains several conserved Cys and His residues, which may suggest stabilization of the domain structure with an embedded short zinc-binding loop [1].
This family covers the N-terminal region of the coronavirus RNA-directed RNA Polymerase which corresponds to the nonstructural protein 12 (NSP12) produced by cleavage of ORF1b. NSP12 contains a polymerase domain that assumes a structure resembling a cupped 'right hand', similar to other polymerases, containing a fingers domain, a palm domain and a thumb domain. Coronavirus NSP12 also contains a nidovirus-unique N-terminal extension that possesses a kinase-like fold allowing the binding of NSP12 to NSP7 and NSP8. NSP12 possesses some minimal activity on its own, but the addition of the NSP7 and NSP8 co-factors greatly stimulates polymerase activity [1].
Iron (II)/2-oxoglutarate (2-OG)-dependent oxygenases catalyse oxidative reactions in a range of metabolic processes. Proline 3-hydroxylase hydroxylates proline at position 3, the first of a 2-OG oxygenase catalysing oxidation of a free alpha-amino acid. The structure of proline 3-hydroxylase contains the conserved motifs present in other 2-OG oxygenases including a jelly roll strand core and residues binding iron and 2-oxoglutarate, consistent with divergent evolution within the extended family. This family represent the arginine, asparagine and proline hydroxylases. The aspartyl/asparaginyl beta-hydroxylase (EC:1.14.11.16) specifically hydroxylates one aspartic or asparagine residue in certain epidermal growth factor-like domains of a number of proteins [1].
The clip domain is a structural/regulatory unit in many arthropod serine proteases [1]. The clip domain super-family also includes serine protease homologs (SPHs) [2]. This entry describes clip domains in the SPHs (CLIP subfamily A), which belong to group-3. SPHs usually carry between 1 to 5 clip domains [3]. The most prominent family member of carrying this clip domain is Scarface proteins in drosophila, which bear an inactive catalytic site, representing a subgroup of serine protease homologues (SPH). Loss-of-function induces defects in JNK-controlled morphogenetic events such as embryonic dorsal closure and adult male terminalia rotation [4].
This domain forms an insert in bacterial beta-glucosidases and is found in other glycosidases, glycosyltransferases, proteases, amidases, yeast adhesins, and bacterial toxins, including anthrax protective antigen (PA). The domain also occurs in a Dictyostelium prespore-cell-inducing factor Psi and in fibrocystin, the mammalian protein whose mutation leads to polycystic kidney and hepatic disease. The crystal structure of PA shows that this domain (named PA14 after its location in the PA20 pro-peptide) has a beta-barrel structure. The PA14 domain sequence suggests a binding function, rather than a catalytic role. The PA14 domain distribution is compatible with carbohydrate binding.
This is the C-terminal domain of the EscN protein family of ATPases that form part of the Type III secretion system (T3SS) present in Escherichia coli. T3SS is a macromolecular complex that creates a syringe-like apparatus extending from the bacterial cytosol across three membranes to the eukaryotic cytosol. This process is essential for pathogenicity. EscN is a functionally unique ATPase that provides an inner-membrane recognition gate for the T3SS chaperone-virulence effector complexes as well as a potential source of energy for their subsequent secretion.The C-terminal domain of T3SS ATPases mediates binding with multiple contact points along the chaperone [1].
This is the C-terminal domain of 1-Cys peroxiredoxin (1-cysPrx), a member of the peroxiredoxin superfamily which protect cells against membrane oxidation through glutathione (GSH)-dependent reduction of phospholipid hydroperoxides to corresponding alcohols [1]. The C-terminal domain is crucial for providing the extra cysteine necessary for dimerisation of the whole molecule. Loss of the enzyme's peroxidase activity is associated with oxidation of the catalytic cysteine, upstream of this domain; and glutathionylation, presumably through its disruption of protein structure, facilitates access for GSH, resulting in spontaneous reduction of the mixed disulfide to the sulfhydryl and consequent activation of the enzyme [2]. The domain is associated with family AhpC-TSA, Pfam:PF00578, which carries the catalytic cysteine.
This domain is widely distributed in all domains of life and occur in stand-alone form and as C-terminal fusions to pantothenate kinase (PanK) in plants and animals. They are metal-dependent phosphatases involved in metabolic damage-control processes termed "damage pre-emption" or "housecleaning". S.cerevisiae Damage-control phosphatase YMR027W and the human orthologue Damage-control phosphatase ARMT1 (also known as C6orf211) are involved in response to DNA damage, a damage pre-emption function. Crystal structure of Damage-control phosphatase At2g17340 from Arabidopsis revealed a novel protein fold and several conserved residues coordinating a metal ion (probably Mg2+), which exhibits a high degree of conservation, suggesting that the metal-binding site is central for the function [1].
This is the N-terminal domain of fungal and eukaryotic Sec3 proteins. Sec3 is a component of the exocyst complex that is involved in the docking of exocytic vesicles with fusion sites on the plasma membrane.This N-terminal domain contains a cryptic pleckstrin homology (PH) fold, and all six positively charged lysine and arginine residues in the PH domain predicted to bind the PIP2 head group are conserved. The exocyst complex is essential for many exocytic events, by tethering vesicles at the plasma membrane for fusion. In fission yeast, polarised exocytosis for growth relies on the combined action of the exocyst at cell poles and myosin-driven transport along actin cables [1].
Pitcher plants are insectivorous and secrete a digestive fluid into the pitcher. This fluid contains a mixture of enzymes including peptidases. One of these is neprosin, characterized from the pitcher plant Nepenthes ventrata. This peptidase is of unknown catalytic type and is unaffected by standard peptidase inhibitors. Unusually, activity is directed towards prolyl bonds, but unlike most peptidase that cleave after proline, there is no restriction on sequence length or position of the proline residue. The peptidase is secreted and is presumed to possess an N-terminal activation peptide. The neprosin domain corresponds to the mature peptidase [1]. It is not known if other proteins with this domain are peptidases.
This family consist of trehalose-phosphatases EC:3.1.3.12 these enzyme catalyse the de-phosphorylation of trehalose-6-phosphate to trehalose and orthophosphate. The aligned region is present in trehalose-phosphatases and comprises the entire length of the protein it is also found in the C-terminus of trehalose-6-phosphate synthase EC:2.4.1.15 adjacent to the trehalose-6-phosphate synthase domain - Pfam:PF00982. It would appear that the two equivalent genes in the E. coli otsBA operon [2] otsA the trehalose-6-phosphate synthase and otsB trehalose-phosphatase (this family) have undergone gene fusion in most eukaryotes e.g. Swiss:P31688 and Swiss:P93653. Trehalose is a common disaccharide of bacteria, fungi and invertebrates that appears to play a major role in desiccation tolerance [1].
Apc4 is one of the larger of the subunits of the anaphase-promoting complex or cyclosome. This family represents the long domain downstream of the WD40 repeat/s that are present on the Apc4 subunits. The anaphase-promoting complex is a multiprotein subunit E3 ubiquitin ligase complex that controls segregation of chromosomes and exit from mitosis in eukaryotes [1,2]. Results in C.elegans show that the primary essential role of the spindle assembly checkpoint is not in the chromosome segregation process itself but rather in delaying anaphase onset until all chromosomes are properly attached to the spindle. the APC/C is likely to be required for all metaphase-to-anaphase transitions in a multicellular organism [3].
Biotin synthase (BioB), EC:2.8.1.6 , catalyses the last step of the biotin biosynthetic pathway. The reaction consists in the introduction of a sulphur atom into dethiobiotin. BioB functions as a homodimer [1]. Thiamin synthesis if a complex process involving at least six gene products (ThiFSGH, ThiI and ThiJ). Two of the proteins required for the biosynthesis of the thiazole moiety of thiamine (vitamin B(1)) are ThiG and ThiH (this family) and form a heterodimer[2]. Both of these reactions are thought of involve the binding of co-factors, and both function as dimers [1,2]. This domain therefore may be involved in co-factor binding or dimerisation (Finn, RD personal observation).
This family constitutes the mitochondrial ATP synthase epsilon subunit. This is not to be confused with the bacterial epsilon subunit, which is homologous to the mitochondrial delta subunit (Pfam:PF00401 and Pfam:PF02823) The epsilon subunit is located in the extrinsic membrane section F1, which is the catalytic site of ATP synthesis. The epsilon subunit was not well ordered in the crystal structure of bovine F1 [1], but it is known to be located in the stalk region of F1 [2]. E subunit is thought to be involved in the regulation of ATP synthase, since a null mutation increased oligomycin sensitivity and decreased inhibition by inhibitor protein IF1 [2].
This family represents the N-terminal region of Pescadillo. Pescadillo protein localises to distinct substructures of the interphase nucleus including nucleoli, the site of ribosome biogenesis. During mitosis pescadillo closely associates with the periphery of metaphase chromosomes and by late anaphase is associated with nucleolus-derived foci and prenucleolar bodies. Blastomeres in mouse embryos lacking pescadillo arrest at morula stages of development, the nucleoli fail to differentiate and accumulation of ribosomes is inhibited. It has been proposed that in mammalian cells pescadillo is essential for ribosome biogenesis and nucleologenesis and that disruption to its function results in cell cycle arrest [1]. This family is often found in conjunction with a Pfam:PF00533 domain.
This is a family of bifunctional enzymes catalysing the last two steps in de novo purine biosynthesis. The bifunctional enzyme is found in both prokaryotes and eukaryotes. The second last step is catalysed by 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase EC:2.1.2.3 (AICARFT), this enzyme catalyses the formylation of AICAR with 10-formyl-tetrahydrofolate to yield FAICAR and tetrahydrofolate [1]. This is catalysed by a pair of C-terminal deaminase fold domains in the protein [3], where the active site is formed by the dimeric interface of two monomeric units [3]. The last step is catalysed by the N-terminal IMP (Inosine monophosphate) cyclohydrolase domain EC:3.5.4.10 (IMPCHase), cyclizing FAICAR (5-formylaminoimidazole-4-carboxamide ribonucleotide) to IMP [1].
This family consists of a domain with a flavodoxin-like fold. The family includes bacterial and eukaryotic NAD(P)H dehydrogenase (quinone) EC:1.6.99.2. These enzymes catalyse the NAD(P)H-dependent two-electron reductions of quinones and protect cells against damage by free radicals and reactive oxygen species [1]. This enzyme uses a FAD co-factor. The equation for this reaction is:- NAD(P)H + acceptor <=> NAD(P)(+) + reduced acceptor. This enzyme is also involved in the bioactivation of prodrugs used in chemotherapy [1]. The family also includes acyl carrier protein phosphodiesterase EC:3.1.4.14. This enzyme converts holo-ACP to apo-ACP by hydrolytic cleavage of the phosphopantetheine residue from ACP [2]. This family is related to Pfam:PF03358 and Pfam:PF00258.
This family consists of several mammalian liver-expressed antimicrobial peptide 2 (LEAP-2) sequences. LEAP-2 is a cysteine-rich, and cationic protein. LEAP-2 contains a core structure with two disulfide bonds formed by cysteine residues in relative 1-3 and 2-4 positions. LEAP-2 is synthesised as a 77-residue precursor, which is predominantly expressed in the liver and highly conserved among mammals. The largest native LEAP-2 form of 40 amino acid residues is generated from the precursor at a putative cleavage site for a furin-like endoprotease. In contrast to smaller LEAP-2 variants, this peptide exhibits dose-dependent antimicrobial activity against selected microbial model organisms [1]. The exact function of this family is unclear.
This is the C-terminal domain found in archaeal type 2 DNA topoisomerase 6 subunit B (EC:5.99.1.3). This region is a small helix-two turns-helix (H2TH) domain inserted between the GHKL and transducer domains which adopts an immunoglobulin-like fold. Mutation analysis of this C-terminal domain showed that the overall activity of the mutant mesophilic methanogen M. mazei Top6B (MmT6) is modestly reduced but its relative activity on different substrates is not affected. Due to the similarity of the B subunit's CTD to known protein- and carbohydrate-binding modules, it has been suggested that it could regulate topo VI spatially, perhaps by localizing the enzyme to a specific subcellular region or functional partner [1].
This domain represents the C-terminal region of the Neuromedin-U receptor 2, a rhodopsin-like GPCR member. It contains two potential casein kinase II phosphorylation sites at threonines residues and one protein kinase C phosphorylation site at a serine residue, which are important to regulate the receptor functionality. This receptor is predominantly expressed in the central nervous system, particularly in the medulla oblongata, pontine reticular formation, spinal cord and thalamus, as its physiological roles are related to modulation of sensory function, neuroendocrine control, food intake as well as with circadian rhythm. However, peripheral expression of this receptor has been determined and includes kidney (medulla), lung and trachea [1-3].
This family consists of dimethylamine methyltransferases from the genus Methanosarcina. It is found in three nearly identical copies in each of Methanosarcina acetivorans, Methanosarcina barkeri, and Methanosarcina mazei. It is one of a suite of three non-homologous enzymes with a critical UAG-encoded pyrrolysine residue in these species (along with trimethylamine methyltransferase and monomethylamine methyltransferase). It demethylates dimethylamine, leaving monomethylamine, and methylates the prosthetic group of the small corrinoid protein MtbC. The methyl group is then transferred by methylcorrinoid:coenzyme M methyltransferase to coenzyme M. Note that the pyrrolysine residue is variously translated as K or X, or as a stop codon that truncates the sequence.
This is a flavin reductase family consisting of enzymes known to be flavin reductases as well as various oxidoreductase and monooxygenase components. VlmR is a flavin reductase that functions in a two-component enzyme system to provide isobutylamine N-hydroxylase with reduced flavin and may be involved in the synthesis of valanimycin [1]. SnaC is a flavin reductase that provides reduced flavin for the oxidation of pristinamycin IIB to pristinamycin IIA as catalysed by SnaA, SnaB heterodimer [2]. This flavin reductase region characterised by enzymes of the family is present in the C-terminus of potential FMN proteins from Synechocystis sp. suggesting it is a flavin reductase domain [1].
This entry represents the N-terminal domain cytadhesin P1 from Mycoplasma. Cytadhesins are virulence factor proteins which mediate attachment of bacterial cells to host cells for invasion. P1 forms a transmembrane complex with P40/P90 called the 'Nap', which mediates motility and infectivity [1,2,3]. Structure of P1, revealed that it consists of a large N-terminal domain consisting of seven consecutive beta-sheets each with four antiparallel beta-strands, except for the seventh which has two strands, and adopts a beta-propeller topology [2,3]. Those two strands correspond to the cytoadherence epitope which has important immune properties [3]. The N-terminal domain is highly variable and described as a structured core surrounded by a fuzzy surface [3].
This entry represents the central domain found in archaeal proteins such as DNA double-strand break repair helicase HerA (EC:3.6.4.12). HerA is a helicase which is able to utilise either 3' or 5' single-stranded DNA extensions for loading and subsequent DNA duplex unwinding [1]. It forms a complex with NurA nuclease, this complex has the 5'-3' DNA end resection activity and is essential for cell viability in the crenarchaeon Sulfolobus islandicus [2]. This domain includes the the central RecA-like catalytic core and a flanking four-helix bundle [3]. The function of this prokaryotic domain is unknown. It contains several conserved aspartates and histidines that could be metal ligands.
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 alpha-helical hairpin domain and a C-terminal alpha/beta domain, represented by this family. 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 hereby mediating the transfer of a phosphoryl group to Spo0A, the ultimate transcription factor.
Fibin is a family of eukaryotic proteins expressed in the lateral plate mesoderm of presumptive pectoral fin bud regions. It acts as a signal molecule for the expression of Tbx5, a gene involved in the specification of fore-limb identity [1]. Fibin is found to be expressed in cerebellum, skeletal muscle and many other embryonic as well as adult mouse tissues, suggesting roles in both embryogenesis and in adult life. Although Fibin is routed through the endoplasmic reticulum (ER) no significant evidence for secretion is found. Fibin is post-translationally modified and forms dimers when expressed heterologously and its expression is regulated by a number of cellular signalling pathways [2].
CBM60 is a family of xylan-binding modules found in conjunction with xylanase enzymes in many bacterial species that attack plant cell walls. Xylan is the major hemicellulose component of most plant cell walls, and is one of the most complex carbohydrates targeted by CBMs. CBM60 modules are evolutionarily related to CBM36 domains as both show circular permutation in the beta-barrel folds. CBM60 targets xylan but is also able to bind cellulose and galactan and thus contribute towards breakdown of the plant cell wall. Recognition of the ligand is conferred primarily through the polar interactions of O2 (oxygen) and O3 of a single sugar with a protein-bound calcium ion [1].
This family of proteins is found in bacteria. Family members are approximately 40 amino acids in length. There is a conserved GKAW sequence motif. There is a single completely conserved residue G that may be functionally important. Family members include the Bacillus subtilis cell-division inhibitor, MciZ (mother cell inhibitor of FtsZ) which blocks the assembly of FtsZ. FtsZ (filamentation temperature-sensitive Z) is the bacterial homolog of tubulin. Crystal structure reveals that MciZ binds to the C-terminal polymerization interface of FtsZ, the equivalent of the minus end of tubulin, causing shortening of protofilaments and blocking the assembly of higher-order FtsZ structures. Hence, MciZ provides a capping-based regulatory mechanism for FtsZ [1].
The unusual mucin, epiglycanin, is membrane-bound at the C-terminus but has a long region of this tandem-repeat at the N-terminus [1]. It was the first mucin identified to be associated with the malignant behaviour of carcinoma cells [2]. Mouse Muc21/epiglycanin is thought to be a highly glycosylated molecule, which makes it likely that its function is dependent on its glycoforms. Cells expressing Muc21 are significantly less adherent to each other and to extracellular matrix components than control cells, and this loss of adhesion is mediated by the TR portion of Muc21 [3]. This family also now contains the repeat that was the C. elegans protein of unknown function (DUF801).
This family, interleukin 23 subunit alpha, is a heterodimer consisting of a 40 kDa subunit - p40 - that is shared with IL12 and a unique 19 kDa subunit - p19. IL23 is a pro-inflammatory cytokine that binds to adnectins and thus plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. IL23 signalling on the cell membrane works through the interaction of four proteins, two of which are shared with the IL12-receptor complex; signalling through the cell membrane involves the combined aggregation of at least two receptor components and then the subsequent activation of the Jak/Tyk tyrosine kinases and the family of STAT transcription factors [1,2,3].
This is a RING zinc finger domain found in parkin proteins. Parkin consists of a ubiquitin-like (Ubl) domain and a 60-amino acid linker followed by this domain RING0 and three additional zinc finger domains characteristic of the RBR family. RING0 binds two coordinated zinc atoms at each extremity of the domain with a hairpin. Deletion of RING0 massively derepressed parkin activity supporting the role of RING0 in autoinhibition, point mutations in RING0 (Phe146 to Ala) or RING2 (Phe463 to Ala) both increased parkin activity. The REP (repressor element of parkin) and RING0 domains play a preeminent role in repressing parkin ligase activity through their interactions with RING1 and RING2, respectively [3].
Natural genetic competence in Bacillus subtilis is controlled by quorum-sensing (QS). The ComP- ComA two-component system detects the signalling molecule ComX, and this signal is transduced by a conserved phosphotransfer mechanism. ComX is synthesised as an inactive precursor and is then cleaved and modified by ComQ before export to the extracellular environment [1]. This family includes ComX phermones involved in quorum sensing. Amino acid sequence alignments between the two ComX precursor proteins in B. licheniformis, showed that their conservation is only restricted to the N-terminal ends. Moreover, high diversity in the amino acid sequence in C-terminus marked the pheromone-forming region, where, interestingly, the tryptophan residue is located [2].
This is a non-canonical pleckstrin homology (PH) domain connected to a 16-leucine-rich repeat domain found in CARMIL (CP Arp2/3 complex myosin-I linker) proteins. The PH domain is interconnected with an N-terminal helix (N-helix), residues 10-20 and a C-terminal linker (Linker), residues 129-147 in Swiss:Q6EDY6 . Structural and functional studies indicate that the PH domain involved in direct binding to the PM (plasma membrane) and a HD (helical domain) responsible for antiparallel dimerization and enhancement of CARMIL's membrane-binding activity. Furthermore, it appears that CARMIL's PH domain mediates non-specific binding to the membrane, in contrast to other PH domains that bind polyphosphorylated phosphatidylinositides, which are thought to function as signalling lipids [1].
This family consists of several phage terminase large subunit proteins as well as related sequences from several bacterial species. The DNA packaging enzyme of bacteriophage lambda, terminase, is a heteromultimer composed of a small subunit, gpNu1, and a large subunit, TerL (gpA), products of the Nu1 and A genes, respectively. Terminase is involved in the site-specific binding and cutting of the DNA during the DNA packaging process. TerL contains all the catalytic activities required for for DNA maturation and packaging. At the N-terminal (represented in this entry) reside the DNA translocase (packaging) and ATPase activities, while at the C-terminal resides the DNA maturation (nuclease/helicase) catalytic activity [1,2,3,4].
This entry represents the trans-membrane domain (TMD) found in insulin receptor proteins. The TMD of the insulin receptor is within the beta-subunit and contains 23 amino acids. Mutations in the TMD were shown to have effects on receptor biosynthetic processing and kinase activation. Substitution of the entire TMD of the insulin receptor (IR) resulted in constitutive kinase activation in vitro, while replacing the TMD with that of glycophorin A inhibited insulin action. Structural studies show that TMD contains a helix and a kink when it is purified in dodecylphosphocholine (DPC) micelles. The residues 942-948 preceding the TMD have a propensity to be a short helix and may interact with membrane [1].
Polycomb repressive complex 2 (PRC2) carries out the methylation of lysine 27 of histone H3, a hallmark of repressive chromatin. Three core subunits make up the catalytic core of PRC2; the SET domain containing EZH2, the zinc-finger containing SUZ12 and the WD40 repeat protein EED. The complex forms a compact arrangement of three lobes. The middle lobe largely comprises two domains that mark the beginning of the carboxy (C)-terminal region of EZH2 (MCSS and SANT2) and the helical, C-terminal, component of the Suz12 Vefs domain. This entry describes the MCSS (also known as SANT2L) domain. There is one zinc binding (Zn1Cys3His1) which is formed solely by MCSS [1, 2].
Cytosolic phospholipases A2 (cPLA2s) consist of a family of calcium-sensitive enzymes that function to generate lipid second messengers through hydrolysis of membrane-associated glycerophospholipids. In humans, the cPLA2 family contains six isoforms. Structural information of full length cPLA2alpha apo form, shows that it is composed of two domains; an N-terminal Ca2 + binding C2 domain and a C-terminal alpha/beta hydrolase core. This entry describes the N-terminal Ca2+ binding C2 domain which is composed of an eight-stranded antiparallel beta-sandwich consisting of two four-stranded beta-sheets. C2 domains are present in many lipid-binding proteins including Copines, CAPRI and Rabphilin-3A all of which are involved in membrane trafficking [1].
CadC is an integral membrane protein of 512 amino acids comprising an N-terminal cytoplasmic DNA-binding domain, a transmembrane helix, and a C-terminal periplasmic domain. CadC belongs to the ToxR-like regulators that encompass biochemically non-modified one-component systems with similar gross topology, including several low pH-induced transcription regulators. Structural analysis of the C-terminal periplasmic domain indicates that it resembles the sensory domain of a (pH-activated) ToxR-like regulator. Furthermore, it is composed of two subdomains with a cavity at their interface that is suited to accommodate cadaverine, the feedback inhibitor of the Cad system. This is the N-terminal subdomain of the C-terminal periplasmic domain. It is composed of five-stranded beta-sheets [1].
This is a zinc finger domain together with a linker region found in RNF125, a small protein (25kD) that contains a RING domain, three zinc fingers (ZnFs) and a ubiquitin interacting motif (UIM). The C2HC ZnF plays an essential role in the interaction of RNF125 with the E2 UbcH5a, which originates from the requirement of the C2HC-ZnF for the structural stability of the RING domain. A mutation at one of the contact residues in the C2HC-ZnF, a highly conserved M112, resulted in the loss of ubiquitin ligase activity. Furthermore, mutations at the Zn2+ chelating cysteine residues, C100 and C103 of this domain resulted in a loss of activity [1].
The Snf2/Hdac Repressive Complex (SHREC) is the fission yeast nucleosome remodeling and deacetylation (NuRD) equivalent and plays a major role in transcriptional gene silencing (TGS) within S. pombe heterochromatin. SHREC consists of the chromatin remodeler Mit1, the HDAC Clr3, and Clr1 and Clr2 proteins. The Mit1 C terminus contains two zinc binding motifs (CCHC zinc fingers) at the C-terminus onto which the alpha helices from both Clr1 and Mit1 pack. The Mit1 chromatin remodeler uses its C-terminal domain to intimately bind to the N-terminal half of Clr1 to integrate into the SHREC complex. This is entry represents the second C-terminal zinc-binding domain found on Mit-1 [1].
The Snf2/Hdac Repressive Complex (SHREC) is the fission yeast nucleosome remodeling and deacetylation (NuRD) equivalent and plays a major role in transcriptional gene silencing (TGS) within S. pombe heterochromatin. SHREC consists of the chromatin remodeler Mit1, the HDAC Clr3, and Clr1 and Clr2 proteins. The Mit1 C terminus contains two zinc binding motifs (CCHC zinc fingers) at the C-terminus onto which the alpha helices from both Clr1 and Mit1 pack. The Mit1 chromatin remodeler uses its C-terminal domain to intimately bind to the N-terminal half of Clr1 to integrate into the SHREC complex. This is entry represents the first C-terminal zinc-binding domain found on Mit-1 [1].
This family contains several mammalian sclerostin (SOST) proteins. SOST is thought to suppress bone formation. Mutations of the SOST gene lead to sclerosteosis, a progressive sclerosing bone dysplasia with an autosomal recessive mode of inheritance. Radiologically, it is characterised by a generalised hyperostosis and sclerosis leading to a markedly thickened and sclerotic skull, with mandible, ribs, clavicles and all long bones also being affected. Due to narrowing of the foramina of the cranial nerves, facial nerve palsy, hearing loss and atrophy of the optic nerves can occur. Sclerosteosis is clinically and radiologically very similar to van Buchem disease, mainly differentiated by hand malformations and a large stature in sclerosteosis patients [1].
MuvB transcriptional regulatory complex interacts with B-Myb to form the MMB complex during S-phase of the cell cycle to activate genes required for the G2 and M phases. This is a domain found at the C-terminal of LIN9, one of the core members of the MuvB complex that functions as a scaffold protein and forms a subcomplex with the C-terminal of LIN152. This subcomplex forms a binding interface that recruits B-Myb to the MuvB complex which is arranged as a three-stranded antiparallel coiled-coil as the core of the structure. LIN9 contributes two helices (alpha1 and alpha2) that run antiparallel and are connected through a short linker [1].
This is an SH3 domain found in antirepressor proteins such as CarS from Myxococcus xanthus. CarS antirepressor recognizes and neutralizes its cognate repressors to turn on a photo-inducible promoter. CarS physically interacts with the MerR-type winged-helix DNA-binding domain of these repressors leading to activation of carB operon. Structural studies of CarS from M. Xanthus reveals a beta-barrel fold akin to that in SH3 domains. However, it diverges from the typical SH3 domain fold in the lengths and conformations of the connecting loops. Functional analysis reveal that SH3 domain-like fold in the antirepressor CasS, mimics operator DNA in sequestering the repressor DNA recognition helix to activate transcription [1].
This domain represents the region comprised between residues 522 and 583 from fission yeast protein Atg11, which is necessary and sufficient for Atg11 autophagy function and for supporting Atg1 kinase activity as it harbours an Atg1-binding domain at the N-terminal and a homodimerisation domain at the C-terminal. The N-terminal part contains the conserved aromatic residues Phe and Tyr necessary for the direct and specific interaction with the tMIT domain of Atg1. This interaction is required for the autophagy function of Atg11. The C-terminal part of this domain, residues 546-583, is predicted to adopt a coiled-coil conformation which mediates Atg11 homodimerisation [1]. It seems to be conserved among Schizosaccharomyces.
This is the N-terminal domain of regulatory factor X (RFX)-5 protein of the RFX complex present in Homo sapiens. The RFX complex is made up of RFX5, RFXAP and RFXB. The complex is involved in the regulation of the expression of the major histocompatibility complex class II (MHCII) gene products. These gene products are essential for the initiation and regulation of the mammalian immune response. The N-terminal domain of RFX5 is responsible for homodimerization of RFX5 which promotes folding of the C-terminal domain of RFXAP. The folding of RFXAP results in the formation of a potential binding site for RFXB to bind to the MHCII promoter [1].
This family consists of several Euplotes raikovi mating pheromone proteins. Diffusible polypeptide pheromones, which distinguish otherwise morphologically identical vegetative cell types from one another, are produced by some species of ciliates. In the marine sand-dwelling protozoan ciliate Euplotes raikovi, pheromone molecules promote the vegetative reproduction (mitogenic proliferation or growth) of the same cells from which they originate. As, understandably, such autocrine pheromone activity is primary to that of targeting and inducing a foreign cell to mate (paracrine functions), this finding provides an example of how the original function of a molecule can be obscured during evolution by the acquisition of a new one [1].
This family represents a conserved domain which is found in a number of eukaryotic proteins including CED-12, ELMO I and ELMO II. ELMO1 is a component of signalling pathways that regulate phagocytosis and cell migration and is the mammalian orthologue of the C. elegans gene, ced-12. CED-12 is required for the engulfment of dying cells and cell migration. In mammalian cells, ELMO1 interacts with Dock180 as part of the CrkII/Dock180/Rac pathway responsible for phagocytosis and cell migration. ELMO1 is ubiquitously expressed, although its expression is highest in the spleen, an organ rich in immune cells [1]. ELMO1 has a PH domain and a polyproline sequence motif at its C terminus which are not present in this alignment.
This is the C-terminal domain found in components of the gamma-tubulin complex proteins (GCPs). Family members include spindle pole body (SBP) components such as Spc97 and Spc98 which function as the microtubule-organizing center in yeast [1]. Furthermore, family members such as human GCP4 (Gamma-tubulin complex component 4) have been structurally elucidated Swiss:Q9UGJ1 . Structure-based sequence analysis revealed the existence of an exposed surface area conserved in all human GCPs and in GCP4 orthologs. This area is located in the C-terminal domain of GCP4, which was confirmed in vitro to bind directly to gamma-tubulin. Sequence alignment of human GCPs based on the GCP4 structure helped delineate conserved regions in the N- and C-terminal domains [2].
This represents a family of archaeal, bacterial and eukaryotic glycosyl hydrolases, that belong to superfamily GH116. The primary catabolic pathway for glucosylceramide is catalysis by the lysosomal enzyme glucocerebrosidase. In higher eukaryotes, glucosylceramide is the precursor of glycosphingolipids, a complex group of ubiquitous membrane lipids [1]. Mutations in the human protein cause motor-neurone defects in hereditary spastic paraplegia [3]. The catalytic nucleophile, identified in UniProtKB:Q97YG8_SULSO, is a glutamine-335, with the likely acid/base at Asp-442 and the aspartates at Asp-406 and Asp-458 residues also playing a role in the catalysis of glucosides and xylosides that are beta-bound to hydrophobic groups. The family is defined as GH116, which presently includes enzymes with beta-glucosidase, EC:3.2.1.21, beta-xylosidase, EC:3.2.1.37, and glucocerebrosidase EC:3.2.1.45 activity [1,2].
This domain is found in bacteria, archaea and eukaryotes. This domain is typically between 320 to 354 amino acids in length. This domain is found associated with Pfam:PF04685. It is found just after the extreme N terminus. The N-terminal is thought to be the luminal domain while the C terminal is the cytosolic domain. The catalytic domain of GBA-2 is unknown. The primary catabolic pathway for glucosylceramide is catalysis by the lysosomal enzyme glucocerebrosidase. In higher eukaryotes, glucosylceramide is the precursor of glycosphingolipids, a complex group of ubiquitous membrane lipids [1]. Mutations in the human protein cause motor-neurone defects in hereditary spastic paraplegia [2,3]. The catalytic nucleophile, identified in UniProtKB:Q97YG8_SULSO, is a glutamine-335 in the downstream family Pfam:PF04685 [4].
This family consists of several scavenger mRNA decapping enzymes (DcpS) and is the C-terminal region. DcpS is a scavenger pyrophosphatase that hydrolyses the residual cap structure following 3' to 5' decay of an mRNA. The association of DcpS with 3' to 5' exonuclease exosome components suggests that these two activities are linked and there is a coupled exonucleolytic decay-dependent decapping pathway. The C-terminal domain contains a histidine triad (HIT) sequence with three histidines separated by hydrophobic residues. The central histidine within the DcpS HIT motif is critical for decapping activity and defines the HIT motif as a new mRNA decapping domain, making DcpS the first member of the HIT family of proteins with a defined biological function.
Phytochromes are red/far-red photochromic biliprotein photoreceptors which regulate plant development. They are widely represented in both photosynthetic and non-photosynthetic bacteria and are known in a variety of fungi. Although sequence similarities are low, this domain is structurally related to Pfam:PF01590 [1], which is generally located immediately N-terminal to this domain. Compared with Pfam:PF01590, this domain carries an additional tongue-like hairpin loop between the fifth beta-sheet and the sixth alpha-helix which functions to seal the chromophore pocket and stabilise the photoactivated far-red-absorbing state (Pfr) [1]. The tongue carries a conserved PRxSF motif, from which an arginine finger points into the chromophore pocket close to ring D forming a salt bridge with a conserved aspartate residue [1].
This entry includes fatty acid and carotene hydroxylases and sterol desaturases. Beta-carotene hydroxylase is involved in zeaxanthin synthesis by hydroxylating beta-carotene, but the enzyme may be involved in other pathways [1]. This family includes C-5 sterol desaturase and C-4 sterol methyl oxidase [2,3,6]. Members of this family are involved in cholesterol biosynthesis and biosynthesis a plant cuticular wax [4]. These enzymes contain two copies of a HXHH motif which coordinate two irons at the catalytic centre. Members of this family are ER integral membrane proteins that share a novel mushroom-shaped fold consisting of four transmembrane (TM1-TM4) helices that anchor them to the membrane capped by a cytosolic domain containing the unique histidine- coordinating di metal centre [5].
N-linked (asparagine-linked) glycosylation of proteins is mediated by a highly conserved pathway in eukaryotes, in which a lipid (dolichol phosphate)-linked oligosaccharide is assembled at the endoplasmic reticulum membrane prior to the transfer of the oligosaccharide moiety to the target asparagine residues. This oligosaccharide is composed of Glc(3)Man(9)GlcNAc(2). The addition of the three glucose residues is the final series of steps in the synthesis of the oligosaccharide precursor. Alg6 transfers the first glucose residue, and Alg8 transfers the second one [1]. In the human alg6 gene, a C->T transition, which causes Ala333 to be replaced with Val, has been identified as the cause of a congenital disorder of glycosylation, designated as type Ic OMIM:603147 [2].
This domain of unknown function is often found at the N-terminus of the bacterial tRNA(Met) cytidine acetyltransferase TmcA. TmcA catalyses the formation of N(4)-acetylcytidine (ac4C) at the wobble position of tRNA(Met) by using acetyl-CoA as an acetyl donor and either ATP or GTP [1,2,5]. This modification is thought to ensure precise recognition of the AUG codon by strengthening C-G base-pair interaction and also prevent misrecognition of the near cognate AUA codon [1]. This domain is also found in mammalian N-acetyltransferase 10 (NAT10) and fungal protein Kre33. Kre33 and NAT10 are RNA cytosine acetyltransferases with specificity toward both 18S rRNA and tRNAs and contain additional putative nuclear and nucleolar localization signals (NLS and NoLS respectively) [3,4,5].
This entry represents a group of deubiquitinating (DUB) enzymes known as the MINDY family (MIU-containing novel DUB). Ubiquitin (Ub) is released one molecule at a time from the distal end of proteins with Lys48-linked polyubiquitin chains. Long polyubiquitin chains are preferred. The catalytic Cys and His residues have been identified by site-directed mutagenesis, as has the Gln that participates in formation of the oxyanion hole during catalysis. Despite the structural similarity to papain-like cysteine peptidases, a residue corresponding to the Asn that orientates the imidazolium ring of the catalytic His has not been identified. Members of the MINDY family of DUBs contain an MIU (motif interacting with Ub) motif, which is a helical motif that binds mono-Ub [1].
GPAT_N is the N-terminal domain of glycerol-3-phosphate acyltransferases, and it forms a four-helix bundle [1]. Glycerol-3-phosphate (1)-acyltransferase(G3PAT) catalyses the incorporation of an acyl group from either acyl-acyl carrier proteins or acyl-CoAs into the sn-1 position of glycerol 3-phosphate to yield 1-acylglycerol-3-phosphate. G3PATs can either be selective, preferentially using the unsaturated fatty acid, oleate (C18:1), as the acyl donor, or non-selective, using either oleate or the saturated fatty acid, palmitate (C16:0), at comparable rates. The differential substrate-specificity for saturated versus unsaturated fatty acids seen within this enzyme family has been implicated in the sensitivity of plants to chilling temperatures [2]. The exact function of this domain is not known. it lies upstream of family Acyltransferase, Pfam:PF01553.
This family represents the BT domain in the methylcrotonoyl-CoA carboxylase subunit alpha, located between the biotin carboxylase (BC) and biotin carboxyl carrier protein (BCCP) domains. This domain mediates crucial interactions between the BC domain in the the alpha subunit and the carboxyltransferase (CT) domain in the beta subunit of this enzyme which are based on ion-pair, hydrogen-bonding and hydrophobic interactions. This domain has a backbone fold with a long helix surrounded by an eight-stranded anti-parallel beta barrel. There is a hook comprising the C-terminal part of the helix and the loop connecting it to the first strand of the beta barrel, which appears to have a central role in alpha and beta subunits interactions [1,2,3].
This family consists of several Drosophila species specific Turandot proteins. The Turandot A (TotA) gene encodes a humoral factor, which is secreted from the fat body and accumulates in the body fluids. TotA is strongly induced upon bacterial challenge, as well as by other types of stress such as high temperature, mechanical pressure, dehydration, UV irradiation, and oxidative agents. It is also up-regulated during metamorphosis and at high age. Flies that over-express TotA show prolonged survival and retain normal activity at otherwise lethal temperatures. Although TotA is only induced by severe stress, it responds to a much wider range of stimuli than heat shock genes such as hsp70 or immune genes such as Cecropin A1 [1].
The island domain in BRI1 corresponds to a large insertion in the regular repeat-structure between LRRs 21 and 22. The resulting 70-residue segment forms a small domain that folds back into the interior of the LRR superhelix, where it makes extensive polar and hydrophobic interactions with LRRs 13-25. The domain fold is characterized by an anti-parallel beta-sheet, which is sandwiched between the LRR core and a 3-10 helix and stabilized by a disulphide bridge. The insertion of a folded domain into the LRR repeat has not been observed in other LRR receptor structures, and is probably an adaptation to the challenge of sensing a small steroid ligand (rather than larger ligands, such as proteins, nucleic acids, or lipids.
Spectrin repeat-domains are found in several proteins involved in cytoskeletal structure. These include spectrin, alpha-actinin and dystrophin. The sequence repeat used in this family is taken from the structural repeat in reference [2]. The spectrin domain- repeat forms a three helix bundle. The second helix is interrupted by proline in some sequences. The repeats are defined by a characteristic tryptophan (W) residue at position 17 in helix A and a leucine (L) at 2 residues from the carboxyl end of helix C. Although the domain occurs in multiple repeats along sequences, the domains are actually stable on their own - ie they act, biophysically, like domains rather than repeats that along function when aggregated.
Type IIS restriction endonuclease FokI is a member of an unusual class of bipartite restriction enzymes that recognises the double-stranded DNA sequence 5'-GGATG-3' and cleave DNA phosphodiester groups 9 base pairs away on this strand and 13 base pairs away on the complementary strand [1]. FokI contains amino- and carboxy-terminal domains corresponding to the DNA- recognition and cleavage functions, respectively. The recognition domain is made of three smaller subdomains (D1, D2 and D3) which are evolutionarily related to the helix-turn-helix-containing DNA-binding domain of the catabolite gene activator protein CAP [3]. This entry represents the subdomain D2 of FokI. D1 and D2 make almost all of the base-specific contacts with the DNA [3].
Members of this family include CDC3, CDC10, CDC11 and CDC12/Septin. Members of this family bind GTP. As regards the septins, these are polypeptides of 30-65kDa with three characteristic GTPase motifs (G-1, G-3 and G-4) that are similar to those of the Ras family. The G-4 motif is strictly conserved with a unique septin consensus of AKAD. Most septins are thought to have at least one coiled-coil region, which in some cases is necessary for intermolecular interactions that allow septins to polymerise to form rod-shaped complexes. In turn, these are arranged into tandem arrays to form filaments. They are multifunctional proteins, with roles in cytokinesis, sporulation, germ cell development, exocytosis and apoptosis [2].
Members of his family are involved in the 1,2 rearrangement of the terminal amino group of DL-lysine and of L-beta-lysine, using adenosylcobalamin (AdoCbl) and pyridoxal-5'-phosphate as co-factors. The structure is predominantly a PLP-binding TIM barrel domain, with several additional alpha-helices and beta-strands at the N and C termini. These helices and strands form an intertwined accessory clamp structure that wraps around the sides of the TIM barrel and extends up toward the Ado ligand of the Cbl co-factor, providing most of the interactions observed between the protein and the Ado ligand of the Cbl, suggesting that its role is mainly in stabilising AdoCbl in the precatalytic resting state [1]. This is a TIM-barrel domain.
This family represents the N-terminal region of Hpr Serine/threonine kinase PtsK. This kinase is the sensor in a multicomponent phospho-relay system in control of carbon catabolic repression in bacteria [1]. This kinase in unusual in that it recognises the tertiary structure of its target and is a member of a novel family unrelated to any previously described protein phosphorylating enzymes [1]. X-ray analysis of the full-length crystalline enzyme from Staphylococcus xylosus at a resolution of 1.95 A shows the enzyme to consist of two clearly separated domains that are assembled in a hexameric structure resembling a three-bladed propeller. The blades are formed by two N-terminal domains each, and the compact central hub assembles the C-terminal kinase domains [2].
Bacterial polysulfide reductase is an integral membrane protein complex responsible for quinone-coupled reduction of polysulfide, a process important in extreme environments such as deep-sea vents and hot springs. Polysulfides are a class of compounds composed of chains of sulfur atoms, which in their simplest form are present as an anion with general formula Sn(2-). In nature, polysulfides are found in particularly high concentrations in extreme volcanic or geothermically active environments. Here, the reduction and oxidation of polysulfides are vital processes for many bacteria and are essential steps in the global sulfur cycle. In particular, the reduction of polysulfide to hydrogen sulfide in these environments is usually linked to energy-generating respiratory processes, supporting growth of many microorganisms, particularly hyperthermophiles.
Small-conductance Ca2+-activated K+ channels (SK channels) are independent of voltage and gated solely by intracellular Ca2+. These membrane channels are heteromeric complexes that comprise pore-forming alpha-subunits and the Ca2+-binding protein calmodulin (CaM) [1]. CaM binds to the SK channel through this the CaM-binding domain (CaMBD), which is located in an intracellular region of the alpha-subunit immediately carboxy-terminal to the pore. Channel opening is triggered when Ca2+ binds the EF hands in the N-lobe of CaM. The structure of this domain complexed with CaM is known [1]. This domain forms an elongated dimer with a CaM molecule bound at each end; each CaM wraps around three alpha-helices, two from one CaMBD subunit and one from the other.
This family includes a variety of sulfotransferase enzymes. Chondroitin 6-sulfotransferase catalyses the transfer of sulfate to position 6 of the N-acetylgalactosamine residue of chondroitin. This family also includes Heparan sulfate 2-O-sulfotransferase (HS2ST) and Heparan sulfate 6-sulfotransferase (HS6ST). Heparan sulfate (HS) is a co-receptor for a number of growth factors, morphogens, and adhesion proteins. HS biosynthetic modifications may determine the strength and outcome of HS-ligand interactions. Mice that lack HS2ST undergo developmental failure only after midgestation,the most dramatic effect being the complete failure of kidney development [1]. Heparan sulphate 6- O -sulfotransferase (HS6ST) catalyses the transfer of sulphate from adenosine 3'-phosphate, 5'-phosphosulphate to the 6th position of the N -sulphoglucosamine residue in heparan sulphate [2].
DIMCO_N is the N-terminal domain of the gamma (Y) subunit of nitrogenase. An alternative name is NafY_N, for nitrogenase accessory factor Y N-terminal. This region is negatively charged and appears to be necessary for recognising and interacting with the apo state of dinitrogenase. The full-length NafY protein facilitates the transfer of iron-molybdenum cofactor, or FeMo-co, into apodinitrogenase by binding to both. The C-terminal region, family Nitro_FeMo-Co, Pfam:PF02579, is the part that binds to the cofactor, and the N-terminus binds to apodinitrogenase. Nitrogenase is the bacterial enzyme responsible for nitrogen fixation by catalysing the reduction of nitrogen gas (N2) to ammonium in an ATP-dependent manner. It has two components, dinitrogenase and dinitrogenase reductase [1].
Fimbriae, also known as pili, form filaments radiating from the surface of the bacterium to a length of 0.5-1.5 micrometres. They enable the cell to colonise host epithelia. This family constitutes the major subunits of CS1 like pili, including CS2 and CFA1 from Escherichia coli, and also the Cable type II pilin major subunit from Burkholderia cepacia [1]. The major subunit of CS1 pili is called CooA. Periplasmic CooA is mostly complexed with the assembly protein CooB. In addition, a small pool of CooA multimers, and CooA-CooD complexes exists, but the functional significance is unknown [1]. A member of this family has also been identified in Salmonella typhi and Salmonella enterica [2].
