This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000345) is described by MIBiG as an example of the following biosynthetic classes, NRP (non-ribosomal peptide) and polyketide. It includes a member from the eponemycin biosynthetic gene cluster from Streptomyces hygroscopicus [
,
]. This family appears to be predominantly found in Actinobacteria.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000700) is described by MIBiG as an example of the following biosynthetic class, saccharide. It includes a member from the istamycin biosynthetic gene cluster from Streptomyces tenjimariensis [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000267) is described by MIBiG as an example of the following biosynthetic classes, polyketide and saccharide. This entry includes a member from the saquayamycin Z biosynthetic gene cluster from Micromonospora sp. Tu 6368 [
]. This family appears to be predominantly found in Actinobacteria.
Transmembrane (TMEM)-176A and 176B proteins are closely related to MS4A (membrane-spanning 4-domains subfamily A) proteins [
]. Their levels are significantly elevated in certain cancers [,
]. TMEM176B (LR8, Torid, Clast1) is broadly expressed, but was up regulated in antigen presenting cells in a rat model of allograft tolerance []. Their role in the immune system is unclear.
This entry includes B-lymphocyte antigen CD20 and other members of the membrane-spanning 4-domains subfamily A (MS4A), and closely related TMEM176 proteins [
,
]. It also includes sarcospan and some uncharacterised proteins. The MS4A family includes the B-cell-specific antigen CD20, hematopoietic-cell-specific protein HTm4, high affinity IgE receptor beta chain (FceRIbeta), and related proteins [
]. Members of this family have four putative transmembrane segments and are predominantly expressed in hematopoietic cells, with important roles in immunity [].Sarcospan is a transmembrane component of dystrophin-glycoprotein complex (DGC), a complex that spans the muscle plasma membrane and forms a link between the F-actin cytoskeleton and the extracellular matrix. Sarcospan preferentially associates with the sarcoglycan subcomplex of the DGC. Loss of the sarcoglycan complex and sarcospan alone is sufficient to cause muscular dystrophy. The role of the sarcoglycan complex and sarcospan is thought to be to strengthen the dystrophin axis connecting the basement membrane with the cytoskeleton [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001931) is described by MIBiG as an example of the following biosynthetic class, polyketide. It includes a member from the carrimycin biosynthetic gene cluster from unidentified unclassified sequences. This family appears to be predominantly found in Actinobacteria.
This domain superfamily is found in several ATP-binding proteins, including: histidine kinase [
], DNA gyrase B, topoisomerases [], heat shock protein HSP90 [,
,
], phytochrome-like ATPases and DNA mismatch repair proteins. The fold of this domain consists of two layers, alpha/beta, which contains an 8-stranded mixed β-sheet.
This family consists of several eukaryotic apyrase (or adenosine diphosphatase) proteins (
), and related nucleoside diphosphatases (
). The salivary apyrases of blood-feeding arthropods are nucleotide hydrolysing enzymes implicated in the inhibition of host platelet aggregation through the hydrolysis of extracellular adenosine diphosphate [
,
]. Soluble calcium-activated nucleotidase 1 (CANT1) is the human homologue [].
The L27 domain is a ~50-amino acid module, initially identified in the Lin-2
and Lin-7 proteins, that exists in a large family of animal scaffold proteins[
]. The L27 domain is a specific protein-protein interaction module capable of forming heteromeric complexes that can integrate multiple scaffold proteins into supramolecular assemblies required for establishment and maintenance of cell polarity. The L27 domain can be found as a single occurrence or as a duplication in association with other domains such as PDZ,SH3, the guanylate kinase domain or the serine/threonine protein kinase domain.
The main features of the L27 domain are conserved negatively charged residues
and a conserved aromatic amino acid []. Study of individual L27 domains revealed largely unfolded domains that require the formation of obligateheterodimers to achieve well-folded structures. Each L27 domain is composed of
three helices. The two L27 domains heterodimerize by building a compactstructure consisting of a four-helix bundle formed by the first two helices of
each L27 domain and one coiled-coil formed by the third helix of each domain [,
].
TssK is an essential baseplate component of the type VI secretion system, which connects the membrane complex, the baseplate and the tail components [
,
,
].The structure of TssK was solved revealing the proteins organise into a tightly packed trimer [
,
]. Each TssK monomer comprises three domains: an N-terminal β-sandwich domain, a linker and a four-helix-bundle middle domain, and a C-terminal domain. The N-terminal domain of TssK is structurally homologous to the shoulder domain of phage receptor-binding proteins, and the C-terminal domain binds the T6SS membrane complex [].This family includes TssK proteins and TssK homologues ImpJ and vasE.The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath [
]. Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA [].
Signal recognition particle, SRP54 subunit, M-domain superfamily
Type:
Homologous_superfamily
Description:
The signal recognition particle (SRP) is a multimeric protein, which along with its conjugate receptor (SR), is involved in targeting secretory proteins to the rough endoplasmic reticulum (RER) membrane in eukaryotes, or to the plasma membrane in prokaryotes [
,
]. SRP recognises the signal sequence of the nascent polypeptide on the ribosome. In eukaryotes this retards its elongation until SRP docks the ribosome-polypeptide complex to the RER membrane via the SR receptor []. Eukaryotic SRP consists of six polypeptides (SRP9, SRP14, SRP19, SRP54, SRP68 and SRP72) and a single 300 nucleotide 7S RNA molecule. The RNA component catalyses the interaction of SRP with its SR receptor []. In higher eukaryotes, the SRP complex consists of the Alu domain and the S domain linked by the SRP RNA. The Alu domain consists of a heterodimer of SRP9 and SRP14 bound to the 5' and 3' terminal sequences of SRP RNA. This domain is necessary for retarding the elongation of the nascent polypeptide chain, which gives SRP time to dock the ribosome-polypeptide complex to the RER membrane. In archaea, the SRP complex contains 7S RNA like its eukaryotic counterpart, yet only includes two of the six protein subunits found in the eukarytic complex: SRP19 and SRP54 [].This entry represents the M domain superfamily of the 54kDa SRP54 component, a GTP-binding protein that interacts with the signal sequence when it emerges from the ribosome. SRP54 of the signal recognition particle has a three-domain structure: an N-terminal helical bundle domain, a GTPase domain, and the M-domain that binds the 7s RNA and also binds the signal sequence. The extreme C-terminal region is glycine-rich and lower in complexity and poorly conserved between species.These proteins include Escherichia coli and Bacillus subtilis ffh protein (P48), which seems to be the prokaryotic counterpart of SRP54; signal recognition particle receptor alpha subunit (docking protein), an integral membrane GTP-binding protein which ensures, in conjunction with SRP, the correct targeting of nascent secretory proteins to the endoplasmic reticulum membrane; bacterial FtsY protein, which is believed to play a similar role to that of the docking protein in eukaryotes; the pilA protein from Neisseria gonorrhoeae, the homologue of ftsY; and bacterial flagellar biosynthesis protein flhF.
This entry represents the ligand-binding domain found in ephrin type-B receptor 1 (EphB1). Using EphB1 knockout-mice, EphB1 has been shown to be essential to the development of long-term potentiation (LTP) [
], a cellular model of synaptic plasticity, learning and memory formation [,
,
].Class EphB receptors bind to transmembrane ephrin-B ligands. There are six vertebrate EhpB receptors (EphB1-6), which display promiscuous interactions with three ephrin-B ligands [
].Ephrin receptors (EphRs) comprise the largest subfamily of receptor tyrosine kinases (RTKs). EphRs contain a ligand binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling) [
].
This family consists of several short bacterial and phage proteins which are related to the E. coli protein AlpA. AlpA suppresses two phenotypes of a delta lon protease mutant, overproduction of capsular polysaccharide and sensitivity to UV light. AlpA acts as a transcriptional regulator of the slpA gene; activation of slpA transcription is necessary to suppress these phenotypes [
]. Several of the sequences in this family are thought to be DNA-binding proteins.
Nucleoid-associated protein YbaB-like domain superfamily
Type:
Homologous_superfamily
Description:
This entry represents a domain superfamily of DNA-binding proteins. It is restricted to bacteria and plants. Members of this family form homodimers which bind DNA via a tweezer-like structure [
,
,
]. The conformation of the DNA is changed when bound to these proteins []. In bacteria, these proteins may play a role in DNA replication-recovery following DNA damage [
]. The plant form contains an additional N-terminal region that may serve as a transit peptide and shows a close relationship to the cyanobacterial member, suggesting that it is a chloroplast protein.The crystal structure YbaB from Haemophilus influenzae revealed a tight dimer with a three-layer structure (beta/alpha/beta) [
].
This family consists of a number of sequences which are highly similar to the Tir chaperone protein in Escherichia coli. In many Gram-negative bacteria, a key indicator of pathogenic potential is the possession of a specialised type III secretion system, which is utilised to deliver virulence effector proteins directly into the host cell cytosol. Many of the proteins secreted from such systems require small cytosolic chaperones to maintain the secreted substrates in a secretion-competent state. CesT serves a chaperone function for the enteropathogenic Escherichia coli (EPEC) translocated intimin receptor (Tir) protein, which confers upon EPEC the ability to alter host cell morphology following intimate bacterial attachment [
]. This family also contains the chaperone protein sicP [
] and several DspF and related sequences from several plant pathogenic bacteria. The "disease-specific"(dsp) region next to the hrp gene cluster of Erwinia amylovora is required for pathogenicity but not for elicitation of the hypersensitive reaction. DspF and AvrF are small (16kDa and 14kDa) and acidic with predicted amphipathic alpha helices in their C termini; they resemble chaperones for virulence factors secreted by type III secretion systems of animal pathogens [
].This entry also includes Pseudomonas aeruginosa ExsC, which functions as a chaperone for ExsE. It is also part of the regulatory cascade that plays a role in the transcriptional regulation of the type III secretion system (T3SS) [
]. The family also contains a number of proteins from eukaryotic parasites.
Members of this family include YscB of Yersinia and functionally equivalent (but differently named) proteins from type III secretion systems of other pathogens that affect animal cells. In Yersinia pestis, the secretion of effector proteins, termed Yersinia outer proteins (Yops), is regulated by the activity of the YopN/SycN/YscB/TyeA complex. YscB acts, along with SycN (
), as a chaperone for YopN, a key part of a complex that regulates type III secretion so that it responds to contact with the eukaryotic target cell [
,
].
This family includes type III secretion system (T3SS) chaperone proteins similar to Salmonella enterica SicP. In S. enterica, many of its serovars being serious human pathogens, the T3SS allows injection of the effector SptP, a virulence protein that is involved in bacterial invasion into a host cell. Chaperone SicP forms a complex with SptP at an early stage of the effector protein secretion process in order to avoid premature degradation; also, the complex is dissociated at a late stage to secrete only SptP with the help of the ATPase InvC which is part of the related T3SS injectisome [
,
,
].
The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell [
] and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Yersinia spp. secrete an effector protein called YopE through the type III needle []. This acts as a Rho GTPase-activating protein that disrupts the host cell actin cytoskeleton, and is regulated by a chaperone protein called SycE/YerA []. In the absence of the SycE chaperone, YopE is not transported through the needle and remains in the bacterial cytoplasm, so suggesting a crucial role for this moiety []. Both the YopE regulator and SycE/YerA proteins share similarity with the exoenzyme S (ExoS) gene product of Pseudomonas aeruginosa [
]. ExoS has both ADP-ribosylating and GTPase activity, and is implicated as a virulence factor. As type III secretion in Pseudomonas is often associated with systemic and even fatal infections in susceptible patients [], the proteins involved are of interest as vaccine and drug targets.
SBP (for SQUAMOSA-pROMOTER BINDING PROTEIN) domain is a sequence specific DNA-binding domain found in plant proteins [
]. Members of family probably function as transcription factors involved in the control of early flower development []. They share a highly conserved DNA-binding domain that contains two zinc-binding sites. Among the 11 possible ligands for the zinc atoms that are conserved in the SBP zinc finger, only 8 are used. The SBP zinc finger follows the general pattern C-x4-C-x16-C-x2-[HC]-x15-C-x2-C-x3-H-x11-C. Three other histidines are well conserved but not involved in zinc binding [
,
].In vitro experiments show that the SBP zinc finger preferentially binds the
consensus sequence -TNCGTACAA- []. However, little is known of the physiological functions of these putative transcriptional regulators beyond their ability to bind DNA.The solution structure of the SBP zinc finger has been solved
[]. The first four Cys or His coordinate one zinc ion and the last four coordinate the other. It can be viewed as two structural subdomains, each subdomain containing a single zinc-binding pocket. The N-terminal subdomain consists of two short alpha helices whereas the C-terminal one contains a three-stranded antiparallel β-sheet.
This family consists of several bacterial NnrS like proteins. NnrS is a haem-Cu protein (NnrS) and a member of the short-chain dehydrogenase family [
]. Expression of nnrS is dependent on the transcriptional regulator NnrR, which also regulates expression of genes required for the reduction of nitrite to nitrous oxide, including nirK and nor. NnrS is a haem- and copper-containing membrane protein. Genes encoding putative orthologues of NnrS are sometimes but not always found in bacteria encoding nitrite and/or nitric oxide reductase []. NnrS contributes to nitrosative-stress tolerance in V. cholerae and protects the cellular iron pool from the formation of dinitrosyl iron complexes (DNICs), thus protecting critical metabolic pathways from inhibition [,
].
Avidin [
] is a minor constituent of egg white in several groups of oviparous vertebrates. Avidin, which was discovered in the 1920's, takes its name from the avidity with which it binds biotin. These two molecules bind so strongly that is extremely difficult to separate them. Streptavidin is a protein produced by Streptomyces avidinii which also binds biotin and whose sequence is evolutionary related to that of avidin.Avidin and streptavidin both form homotetrameric complexes of noncovalently associated chains. Each chain forms a very strong and specific non-covalent complex with one molecule of biotin. The three-dimensional structures of both streptavidin [
,
] and avidin [] have been determined and revealed them to share a common fold: an eight stranded anti-parallel β-barrel with a repeated +1 topology enclosing an internal ligand binding site.Fibropellins I and III [
] are proteins that form the apical lamina of the sea urchin embryo, a component of the extracellular matrix. These two proteins have a modular structure composed of a CUB domain (see), followed by a variable number of EGF repeats and a C-terminal avidin-like domain.
This family consists of several Chordopoxvirus A20R proteins. The A20R protein is required for DNA replication, is associated with the processive form of the viral DNA polymerase, and directly interacts with the viral proteins encoded by the D4R, D5R, and H5R open reading frames. A20R may contribute to the assembly or stability of the multiprotein DNA replication complex [
].
This entry represents various uracil-DNA glycosylases and related DNA glycosylases (
), such as uracil-DNA glycosylase [
], thermophilic uracil-DNA glycosylase [], G:T/U mismatch-specific DNA glycosylase (Mug) [], and single-strand selective monofunctional uracil-DNA glycosylase (SMUG1) []. These proteins have a 3-layerα/β/α structure.Uracil-DNA glycosylases are DNA repair enzymes that excise uracil residues from DNA by cleaving the N-glycosylic bond, initiating the base excision repair pathway. Uracil in DNA can arise either through the deamination of cytosine to form mutagenic U:G mispairs, or through the incorporation of dUMP by DNA polymerase to form U:A pairs [
]. These aberrant uracil residues are genotoxic []. The sequence of uracil-DNA glycosylase is extremely well conserved [] in bacteria and eukaryotes as well as in herpes viruses. More distantly related uracil-DNA glycosylases are also found in poxviruses [].
The eukaryotic RNA polymerase subunits RPB4 and RPB7 form a heterodimer that reversibly associates with the RNA polymerase II core, being involved in initiation complex formation [
]. Archaeal cells contain a single RNAP made up of about 12 subunits, displaying considerable homology to the eukaryotic RNAPII subunits. The RPB4 and RPB7 homologues are called subunits F and E, respectively, and have been shown to form a stable heterodimer. While the RPB7 homologue is reasonably well conserved, the similarity between the eukaryotic RPB4 and the archaeal F subunit is barely detectable [].This entry represents the N-terminal, heterodimerisation domain superfamily of RPB7 and homologues. This domain has a beta-α-β(2) fold arranged in two layers (alpha/beta) with antiparallel β-sheet.
This entry represents Tail tip protein M from Escherichia phage lambda (Bacteriophage lambda). Members of this protein family are found in tailed bacteriophages (Caudovirales) and in bacterial prophages mostly among Proteobacteria.TipM is part of the distal tail tip which plays a role in DNA ejection during entry, and in tail assembly initiation during exit. It may bind tail tip complex associated with tape measure protein and allow tail tube protein polymerization on top of tail tip [
].
Carbamoyl-phosphate synthetase, large subunit oligomerisation domain superfamily
Type:
Homologous_superfamily
Description:
This entry represents the oligomerisation domain superfamily found in the large subunit of carbamoyl phosphate synthases as well as in certain other carboxy phosphate domain-containing enzymes. This domain forms a primarily α-helical fold [
].
This entry includes monooxygenase component MmoB methane monooxygenase (
) regulatory protein B and Phenol hydroxylase (
) protein component P2 (DmpM). When MmoB is present at low concentration it converts methane monooxygenase from an oxidase to a hydroxylase and stabilises intermediates required for the activation of dioxygen [
]. DmpM lacks redox co-factors and is required for optimal turnover of Phenol hydroxylase []. Phenol hydroxylase catabolises phenol and some of its methylated derivatives in the first step of phenol biodegradation, and is required for growth on phenol. The multicomponent enzyme is made up of P0, P1, P2, P3, P4 and P5 polypeptides.The common structure for these proteins consists of a corner-like structure formed by two sheets and filled in with 2-3 helices.
DNA integrity scanning protein, DisA, N-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Cyclic di-AMP (c-di-AMP) is a bacterial secondary messenger molecule, which is associated with various physiological functions. It is involved in several important cellular processes, such as cell wall metabolism, maintenance of DNA integrity, ion transport, transcription regulation, and allosteric regulation of enzyme function. The 120-amino acid-long diadenylate cyclase (DAC) domain converts two ATP or ADP molecules into one c-di-AMP molecule. The majority of DAC domain-containing proteins are found in bacterial species, but a small number are also present in archaea of the phylum Euryarchaeota. In bacteria, DAC domain proteins are most frequently found in Gram-positive bacteria belonging to the phyla Firmicutes and Actinobacteria, including pathogenic bacteria such as Listeria monocytogenes or Staphylococcus aureus. Compared with the majority of bacterial species which encode only one DAC enzyme, members of the genus
Bacillusgenerally encode three DAC domain-containing proteins: DisA, CdaA (previously named YbbP in the genus
Bacillusor DacA in other genera) and CdaS (previously named YojJ in the genus
Bacillusor DacB in others) [
,
,
,
,
].The DAC domain exhibits an overall globular alpha/beta fold with the long N-terminally located helix (alpha1) flanking the core. A slightly twisted central β-sheet, made up of seven mixed-parallel and antiparallel β-strands, forms the core globular part. Both sides of the β-sheets are flanked by a total of five α-helices (alpha1-alpha5), resulting in the observed globular shape [
,
].The DisA protein is a bacterial checkpoint protein that dimerises into an octameric complex. The protein consists of three distinct domains. The DAC domain is the first and is a globular, nucleotide-binding region; the next 146-289 residues constitute the DisA-linker family,
that consists of an elongated bundle of three alpha helices (alpha-6, alpha-10, and alpha-11), one side of which carries an additional three helices (alpha7-9), which thus forms a spine like-linker between domains 1 and 3. The C-terminal residues, of domain 3, are represented by family HHH,
the specific DNA-binding domain. The octameric complex thus has structurally linked nucleotide-binding and DNA-binding HhH domains and the nucleotide-binding domains are bound to a cyclic di-adenosine phosphate such that DisA is a specific di-adenylate cyclase. The di-adenylate cyclase activity is strongly suppressed by binding to branched DNA, but not to duplex or single-stranded DNA, suggesting a role for DisA as a monitor of the presence of stalled replication forks or recombination intermediates via DNA structure-modulated c-di-AMP synthesis.
This family consists of several bacterial proteins and includes the Escherichia coli genes for ElaB, YgaM and YqjD.YqjD is an inner membrane and ribosome binding protein expressed during the stationary growth phase. It is possible that YqjD inactivates ribosomes by localizing a part of the ribosome to the membrane during the stationary phase [
]. Its expression is regulated by stress response sigma factor RpoS. The two paralogues of YqjD, ElaB and YgaM, are expressed and bind to ribosomes in a similar manner to YqjD [,
]. These proteins may have important cellular roles during the stress response. ElaB has been shown to protect cells against oxidative and heat shock stress [].
This family consists of several Cytomegalovirus TRL10 proteins. TRL10 represents a structural component of the virus particle and like the other HCMV envelope glycoproteins, is present in a disulphide-linked complex [
].
This family consists of several Orthopoxvirus A26L and A30L proteins. The Vaccinia A30L gene is regulated by a late promoter and encodes a protein of approximately 9kDa. It is thought that the A30L protein is needed for vaccinia virus morphogenesis, specifically the association of the dense viroplasm with viral membranes [
].
This domain family is found in eukaryotes, and is typically between 78 and 110 amino acids in length. The family is found in association with
. There are two completely conserved residues (D and G) that may be functionally important. This family is an 87kDa transposase protein which catalyses both the precise and imprecise excision of a nonautonomous P transposable element.
This entry includes inactive rhomboid proteins (iRhom1/2), which are catalytically inactive rhomboid protease homologues that play crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling [
]. These are metazoan specific pseudoproteases which regulate ADAM17 protease, a sheddase of the epidermal growth factor (EGF) receptor ligands and TNF, acting as trafficking factors that escort ADAM17 from the ER to the later secretory pathway. They are required for the cleavage and release of a variety of membrane-associated proteins []. iRhoms share a common structure comprising 7-helix transmembrane-spanning domains (TMDs) which is a conserved rhomboid fold, an extended N-terminal cytosolic domain and a luminal loop [,
].These proteins have been linked to the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy [
] and also in neurological disorders such as Alzheimer's and Parkinson's diseases, inflammation, cancer and skin diseases [].
This presumed domain is functionally uncharacterised. This domain family is found in bacteria, and is approximately 290 amino acids in length. It contains a BNR/Asp box motif at the C-terminal, which contains the characteristic sequence motif SxDxGxT/xW of the BNR family, present as repeats in sialidases and other glycosyl hydrolases [
].
This family of proteins is functionally uncharacterised and it is found mostly in Firmicutes. There are some conserved sequences: HQK and KWG at the N-terminal, and HNxxW near the C-terminal.
This family of proteins is found in bacteria. Proteins in this family are typically between 108 and 129 amino acids in length. There are two conserved sequence motifs: NDP and RVLT.
This family of bacterial proteins is functionally uncharacterised. Proteins in this family are typically between 969 and 1090 amino acids in length. Some members of this family are thought to be related to the Flagellar hook-length control protein FliK.
This domain family is found in bacterial prophage and viruses, and is typically between 49 and 166 amino acids in length. The family is found in association with
. In T-even phages, Gp37 and Gp38 are components of the tail fibre that are critical for phage-host interaction.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000081) is described by MIBiG as an example of the following biosynthetic class, polyketide. It includes a member from the kedarcidin biosynthetic gene cluster from Streptoalloteichus sp. ATCC 53650 [
,
].
This domain is found in viruses, and is approximately 70 amino acids in length. The family is found in association with
. The Rubella virus (RUB) nonstructural (NS) protein (NSP) ORF encodes a protease that cleaves the NSP precursor (240kDa) at a single site to produce two products.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000703) is described by MIBiG as an example of the following biosynthetic class, saccharide. It includes a member from the kanamycin biosynthetic gene cluster from Streptomyces kanamyceticus [
]. This family appears to be predominantly found in bacteria.
RELT-like protein 2 (RELL2) belongs to the RELT family. Overexpression of RELL2 induces activation of MAPK14/p38 cascade [
].RELT (receptor expressed in lymphoid tissues) is a member of the TNFR superfamily. The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1 [
]. RELT like proteins 1 and 2 (RELL1 and RELL2) are two RELT homologues that bind to RELT. The expression of RELL1 at the mRNA level is ubiquitous, whereas expression of RELL2 mRNA is more restricted to particular tissues [].
RELT-like protein 1 (RELL1) belongs to the RELT family. Its overexpression induces activation of MAPK14/p38 cascade [
].RELT (receptor expressed in lymphoid tissues) is a member of the TNFR superfamily. The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1 [
]. RELT like proteins 1 and 2 (RELL1 and RELL2) are two RELT homologues that bind to RELT. The expression of RELL1 at the mRNA level is ubiquitous, whereas expression of RELL2 mRNA is more restricted to particular tissues [].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001214) is described by MIBiG as an example of the following biosynthetic class, NRP (non-ribosomal peptide). It includes a member from the marformycin A biosynthetic gene cluster from Streptomyces drozdowiczii [
].
This domain family is found in eukaryotes, and is typically between 54 and 99 amino acids in length. The family is found in association with
. CK1gamma is a membrane-bound member of the CK1 family. Gain-of-function and loss-of-function experiments show that CK1gamma is both necessary and sufficient to transduce LRP6 signalling in vertebrates and Drosophila cells.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001432) is described by MIBiG as an example of the following biosynthetic classes, NRP (non-ribosomal peptide) and polyketide. It includes a member from the myxochromide D biosynthetic gene cluster from Stigmatella erecta [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001503) is described by MIBiG as an example of the following biosynthetic class, polyketide. It includes a member from the amycolamycin A biosynthetic gene cluster from Amycolatopsis sp. [
]. This family appears to be predominantly found in Actinobacteria.
This family consists of several radial spoke protein 3 (RSP3) sequences. Eukaryotic cilia and flagella present in diverse types of cells perform motile, sensory, and developmental functions in organisms from protists to humans. They are centred by precisely organised, microtubule-based structures, the axonemes. The axoneme consists of two central singlet microtubules, called the central pair, and nine outer doublet microtubules. These structures are well conserved during evolution. The outer doublet microtubules, each composed of A and B sub-fibres, are connected to each other by nexin links, while the central pair is held at the centre of the axoneme by radial spokes. The radial spokes are T-shaped structures extending from the A-tubule of each outer doublet microtubule to the centre of the axoneme. Radial spoke protein 3 (RSP3), is present at the proximal end of the spoke stalk and helps in anchoring the radial spoke to the outer doublet. It is thought that radial spokes regulate the activity of inner arm dynein through protein phosphorylation and dephosphorylation [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000709) is described by MIBiG as an example of the following biosynthetic class, saccharide. It includes a member from the neomycin biosynthetic gene cluster from Streptomyces fradiae ATCC 10745 = DSM 40063 [
]. This family appears to be predominantly found in Actinobacteria.
This entry represents a member of a biosynthetic gene cluster (BGC0001973 in MIBiG). It includes a member from the fervenulin biosynthetic gene cluster from Streptomyces hiroshimensis [
]. This family appears to be predominantly found in Actinobacteria.
This entry is represented by Bacteriophage P2, GpM. The characteristics of the protein distribution suggest prophage matches in addition to the phage matches.This family consists of several phage small terminase subunit proteins as well as some related bacterial sequences [
]. M protein is probably an endonuclease which directs cos cleavage. The Q, P and M proteins are needed to package DNA into proheads and for the conversion of proheads to capsids.
This family consists of a series of hypothetical bacterial proteins. One of the family members
from Bacillus subtilis is thought to be involved in cell division and sporulation [
].
Glycoside hydrolase family 3 C-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Glycoside hydrolase family 3
comprises enzymes with a number of known activities; beta-glucosidase (
); beta-xylosidase (
); N-acetyl beta-glucosaminidase (
); glucan beta-1,3-glucosidase (
); cellodextrinase(
); exo-1,3-1,4-glucanase (
).
These enzymes are two-domain globular proteins that are N-glycosylated at three sites [
]. This entry represents the C-terminal domain superfamily, involved in catalysis and may be involved in binding beta-glucan []. Its structure has a flavodoxin-like fold, which consists of three layers (alpha/beta/alpha) with parallel β-sheet of five strand.
The majority of the sequences having this domain belong to the MEROPS inhibitor family I2, clan IB; the Kunitz/bovine pancreatic trypsin inhibitor family, they inhibit proteases of the S1 family [
] and are restricted to the metazoa with a single exception: Amsacta moorei entomopoxvirus. They are short (~50 residue)alpha/beta proteins with few secondary structures. The fold is constrained
by 3 disulphide bonds. The type example for this family is aprotinin (bovine pancreatic trypsin inhibitor) [] (or basic protease inhibitor), but the family includes numerous other members
[,
,
,
], such as snake venom basic protease; mammalian inter-alpha-trypsininhibitors; trypstatin, a rodent mast cell inhibitor of trypsin; a domain
found in an alternatively-spliced form of Alzheimer's amyloid beta-protein;domains at the C-termini of the alpha(1) and alpha(3) chains of type VII
and type VI collagens; and tissue factor pathway inhibitor precursor.The pancreatic trypsin inhibitor (Kunitz) family [
,
,
] is one of thenumerous families of serine proteinase inhibitors. The basic structure of
such a type of inhibitor is shown in the following schematic representation:+-----------------------+
| +--------+ || | **|******* |
xxCxxC#xxxCxxxCxxxxxxCxxxxCxx| |
+----------+{------50 residues------}
'C': conserved cysteine involved in a disulfide bond.'#': active site residue.
'*': position of the pattern.
This family consists of toxin-coregulated pilus subunit (TcpA) proteins from Vibrio cholerae and related sequences. The major virulence factors of toxigenic V. cholerae are cholera toxin (CT), which is encoded by a lysogenic bacteriophage (CTXPhi), and toxin-coregulated pilus (TCP), an essential colonisation factor which is also the receptor for CTXPhi. The genes for the biosynthesis of TCP are part of a larger genetic element known as the TCP pathogenicity island [
].
Proteins in this entry are found in archaea and eukaryota, they contain a predicted DNA-binding domain [
] and may function as DNA-binding proteins. Methanobacterium thermoautotrophicum MTH1615 was predicted to bind DNA based on structural proteomics data, and this was confirmed by the demonstration that it can interact non-specifically with a randomly chosen 20-mer of double stranded DNA []. This suggests that the human protein may be involved in nucleic acid binding or metabolism.The human programmed cell death protein 5 (PDCD5, also known as TFAR19) encodes a protein which shares significant homology to the corresponding proteins of species ranging from yeast to mice. PDCD5 exhibits a ubiquitous expression pattern and its expression is up-regulated in the tumour cells undergoing apoptosis. PDCD5 may play a general role in the apoptotic process [
,
].
This entry represents a group of Gram-negative bacterial proteins that form part of the type VI pathogenicity secretion system (T6SS), including TssF [
]. TssF is an essential baseplate component of the type VI secretion system. TssF is a homologue of phage tail proteins and is required for proper assembly of the Hcp tube (the T6SS inner tube) in bacteria [].The cryoEM structure of a TssK-TssF-TssG complex revealed that TssF comprises 3 domains; an α-helical N-terminal domain, a central domain made up of three β-barrels and a C-terminal four-stranded mixed β-sheet packed against α-helices via a hydrophobic core [
]. TssF and TssG assembled into a heterotrimer with 2:1 stoichiometry [,
].The type VI secretion system (T6SS) is a supra-molecular bacterial complex that resembles phage tails. It is a toxin delivery systems which fires toxins into target cells upon contraction of its TssBC sheath [
]. Thirteen essential core proteins are conserved in all T6SSs: the membrane associated complex TssJ-TssL-TssM, the baseplate proteins TssE, TssF, TssG, and TssK, the bacteriophage-related puncturing complex composed of the tube (Hcp), the tip/puncturing device VgrG, and the contractile sheath structure (TssB and TssC). Finally, the starfish-shaped dodecameric protein, TssA, limits contractile sheath polymerization at its distal part when TagA captures TssA [].
This entry represents the beta-α-β-α-β-beta fold found in Alba proteins, which are archaeal and eukaryotic DNA- or RNA-binding
proteins involved in RNA metabolism and have the function of a chromosomal protein in some archaea. This fold is similar to the folds of DNase I and the C-terminaldomain of the translation initiation factor IF3. This fold can also be found in eukaryotic RNase P/RNase MRP components Pop6 and Pop7 [
].
The SWI/SNF family of complexes, which are conserved from yeast to humans, are ATP-dependent chromatin-remodelling proteins that facilitate transcription activation [
,
,
]. The mammalian complexes are made up of 9-12 proteins called BAFs (BRG1-associated factors). The BAF60 family have at least three members: BAF60a, which is ubiquitous, BAF60b and BAF60c, which are expressed in muscle and pancreatic tissues, respectively. BAF60b is present in alternative forms of the SWI/SNF complex, including complex B (SWIB), which lacks BAF60a. The SWIB domain is a conserved region found within the BAF60b proteins [], and can be found fused to the C terminus of DNA topoisomerase in Chlamydia. This domain is also found in the Saccharomyces cerevisiae SNF12 protein, the eukaryotic initiation factor 2 (eIF2) []and the Arabidopsis thaliana At1g31760 protein [].MDM2 is an oncoprotein that acts as a cellular inhibitor of the p53 tumour suppressor by binding to the transactivation domain of p53 and suppressing its ability to activate transcription [
]. p53 acts in response to DNA damage, inducing cell cycle arrest and apoptosis. Inactivation of p53 is a common occurrence in neoplastic transformations. The core of MDM2 folds into an open bundle of four helices, which is capped by two small 3-stranded β-sheets. It consists of a duplication of two structural repeats. MDM2 has a deep hydrophobic cleft on which the p53 α-helix binds; p53 residues involved in transactivation are buried deep within the cleft of MDM2, thereby concealing the p53 transactivation domain.The SWIB and MDM2 domains are homologous and share a common fold. The core of this domain is composed of four helices arranged in an open bundle, capped by two small 3-stranded β-sheets.
The [2Fe-2S] binding domain is found in a range of enzymes including dehydrogenases, oxidases and oxidoreductases.The aldehyde oxido-reductase (Mop) from the sulphate reducing anaerobic Gram-negative bacterium Desulfovibrio gigas is a homodimer of 907 amino acid residues subunits and is a member of the xanthine oxidase family. The protein contains a molybdopterin cofactor (Mo-co) and two different [2Fe-2S] centres. It is folded into four domains of which the first two bind the iron sulphur centres and the last two are involved in Mo-co binding. Mo-co is a molybdenum molybdopterin cytosine dinucleotide. Molybdopterin forms a tricyclic system with the pterin bicycle annealed to a pyran ring. The molybdopterin dinucleotide is deeply buried in the protein. The cis-dithiolene group of the pyran ring binds the molybdenum, which is coordinated by three more (oxygen) ligands [].
The APSES (ASM-1, Phd1, StuA, EFG1, and Sok2) domain is a ~110-residue sequence-specific DNA-binding domain found in a family of fungal transcription factors and other DNA-binding proteins. The APSES domain is found associated with ankyrin repeats (see
,
) and a heterodimerization domain [
,
].The APSES domain consists of a six-stranded β-sheet segment folded against two pairs of α-helices in the topology of the winged helix-turn-helix (HTH) family of proteins [
]. The alphaA/alphaB helical pair corresponds to the HTH motif [,
,
]. Some proteins known to contain an APSES domain are listed below:Saccharomyces cerevisiae (Baker's yeast) Mlu-1 box binding protein (MBP1,
); Mlu-1 and Swi6 together make up the transcription factor complex MBF (Mlu-1-binding factor), which binds to the Mlu1 cell-cycle box (MCB) elements found in the promoters of many DNA synthesis genes [
]. Schizosaccharomyces pombe (Fission yeast) cell division cycle-related proteins res1/sct1 (
) and res2/pct1 (
), which are homologous to MBP1.
S. pombe start control protein cdc10 (
).
Emericella nidulans (Aspergillus nidulans) cell pattern formation-associated protein stuA (
). It regulates the transformation of undifferentiated hyphal elements into a complex multicellular structure.
S. cerevisiae transcription factor PHD1 (
).
S. cerevisiae protein SOK2 (
). It represses the transition from unicellular growth to pseudohyphae.
Candida albicans (Yeast) enhanced filamentous growth protein (EFG1,
)).
Neurospora crassa ascospore maturation 1 protein (Asm-1,
). It has a role in spore maturation.
S. pombe bouquet formation protein 4 (
), which is a nuclear membrane protein that
connects telomeres to the nuclear envelop (NE) during both vegetative growth and meiosis. Bqt4 does not seem to bind DNA, but acts as an adaptor between Bqt3 and Rap1 [].
This family consists of allatostatins, bombystatins, helicostatins, cydiastatins and schistostatin from several insect species. Allatostatins (ASTs) of the Tyr/Phe-Xaa-Phe-Gly Leu/Ile-NH2 family are a group of insect neuropeptides that inhibit juvenile hormone biosynthesis by the corpora allata [
].
Villin is an F-actin bundling protein involved in the
maintenance of the microvilli of the absorptive epithelia. The villin-type "headpiece"domain is a modular motif found at the extreme C terminus of larger "core"domains in over 25 cytoskeletal proteins in plants and animals, often in assocation with the Gelsolin repeat. Although the headpiece is classified as an F-actin-binding domain, it has been shown that not all headpiece domains are intrinsically F-actin-binding motifs, surface charge distribution may be an important element for F-actin recognition [
]. An autonomously folding, 35 residue, thermostable subdomain (HP36) of the full-length 76 amino acid residue villin headpiece, is the smallest known example of a cooperatively folded domain of a naturally occurring protein. The structure of HP36, as determined by NMR spectroscopy, consists of three short helices surrounding a tightly packed hydrophobic core [].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001772) is described by MIBiG as an example of the following biosynthetic class, polyketide, in particular the scytophycin biosynthetic gene cluster from Anabaena sp. UHCC 0451 [
].
This entry represents the ligand-binding domain found in ephrin type-B receptor 4 (EphB4). EphB4 has been implicated in a number of cancers [
,
,
,
]. It has also been shown to play a role in osteoblast differentiation []. Class EphB receptors bind to transmembrane ephrin-B ligands. There are six vertebrate EhpB receptors (EphB1-6), which display promiscuous interactions with three ephrin-B ligands [
].Ephrin receptors (EphRs) comprise the largest subfamily of receptor tyrosine kinases (RTKs). EphRs contain a ligand binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling) [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001417) is described by MIBiG as an example of the following biosynthetic classes, NRP (non-ribosomal peptide) and polyketide, in particular the myxochromide D biosynthetic gene cluster from Cystobacterineae bacterium [
]. This domain family appears to be predominantly found in Cystobacterineae.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000078) is described by MIBiG as an example of the following biosynthetic class, polyketide, in particular the incednine biosynthetic gene cluster from Streptomyces sp. ML694-90F3 [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000699) is described by MIBiG as an example of the following biosynthetic class, saccharide, in particular the hygromycin A biosynthetic gene cluster from Streptomyces hygroscopicus subsp. hygroscopicus [
]. This family appears to be predominantly found in Actinobacteria.
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol [
]. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [
,
,
]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.
Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [
,
].Aquaporin-1 is the major water channel present in the kidney proximal renal tubule. Members of the family contain approximately 275 amino acids. Aquaporin-1 is under complex regulation, including hormones and homeostatic factors like hypertonicity [
]. It is also expressed in red blood cells, the gastrointestinal tract, lungs and in the brain, where it may have a role in cerebral oedema after surgery or trauma []. Apart from controlling the water balance of the organism [,
], aquaporin-1 is thought to have an impact on various cellular processes, such as angiogenesis, and cell migration and metastasis observed in some human malignancies. Its expression has also been proposed as a characteristic feature of an aggressive sub-group of breast carcinomas.
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol [
]. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [
,
,
]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.
Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [
,
].Aquaporin-5 takes part in saliva production [
], the release of tears in the lacrimal glands, and water homeostasis in the lungs. It is water specific and is expressed mainly in the lung epithelium. Aquaporin-5 is therefore connected with certain lung pathologies following lung trauma, and some pathological conditions leading to dysfunction in the salivary and lacrimal glands [].
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol [
]. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [,
,
]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.
Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [
,
].Aquaporin-6 forms a water-specific channel [
] that participates in distinct physiological functions, such as glomerular filtration, tubular endocytosis and acid-base metabolism. It is found in the kidney and gastrointestinal tract [], and is also localised in the inner ear of mammals []. It is a pH-regulated anion channel [], and has been found to bind calmodulin in a calcium-dependent manner, possibly providing a vital clue to its physiological role in the kidney [].
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol [
]. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [
,
,
]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.
Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [
,
].Aquaporin-8 forms a mercury-sensitive water-specific channel [
,
]. It may have an important role in spermatogenesis, in fertilisation, and in the secretion of pancreatic juice and saliva []. It is also found in the liver, in bile canalicular membranes, where it takes part in bile formation [].
Aquaporins are water channels, present in both higher and lower organisms, that belong to the major intrinsic protein family. Most aquaporins are highly selective for water, though some also facilitate the movement of small uncharged molecules such as glycerol [
]. In higher eukaryotes these proteins play diverse roles in the maintenance of water homeostasis, indicating that membrane water permeability can be regulated independently of solute permeability. In microorganisms however, many of which do not contain aquaporins, they do not appear to play such a broad role. Instead, they assist specific microbial lifestyles within the environment, e.g. they confer protection against freeze-thaw stress and may help maintain water permeability at low temperatures []. The regulation of aquaporins is complex, including transcriptional, post-translational, protein-trafficking and channel-gating mechanisms that are frequently distinct for each family member.Structural studies show that aquaporins are present in the membrane as tetramers, though each monomer contains its own channel [
,
,
]. The monomer has an overall "hourglass"structure made up of three structural elements: an external vestibule, an internal vestibule, and an extended pore which connects the two vestibules. Substrate selectivity is conferred by two mechanisms. Firstly, the diameter of the pore physically limits the size of molecules that can pass through the channel. Secondly, specific amino acids within the molecule regulate the preference for hydrophobic or hydrophilic substrates.
Aquaporins are classified into two subgroups: the aquaporins (also known as orthodox aquaporins), which transport only water, and the aquaglyceroporins, which transport glycerol, urea, and other small solutes in addition to water [
,
].This entry represents aquaporin Z, a major water channel protein in bacteria. It mediates water influx in response to large changes in cellular osmorality [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000202) is described by MIBiG as an example of the following biosynthetic class, polyketide.
This domain is functionally uncharacterised. Proteins with this domain are predominantly found in bacteria. This domain family may be distantly related to PF09370 suggesting these proteins may function as an enzyme of unknown activity.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000262) is described by MIBiG as an example of the following biosynthetic classes, polyketide and saccharide, in particular the prejadomycin biosynthetic gene cluster from Streptomyces sp. PGA64 [
,
]. This family appears to be predominantly found in bacteria.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000700) is described by MIBiG as an example of the following biosynthetic class, saccharide, in particular the istamycin biosynthetic gene cluster from Streptomyces tenjimariensis [
]. This family appears to be predominantly found in actinobacteria.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000703) is described by MIBiG as an example of the following biosynthetic class, saccharide, in particular the kanamycin biosynthetic gene cluster from Streptomyces kanamyceticus [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0001381) is described by MIBiG as an example of the following biosynthetic class, polyketide, in particular the brasilinolide A biosynthetic gene cluster from Nocardia terpenica [
]. This family appears to be predominantly found in Actinobacteria.
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0002024) is described by MIBiG as an example of the following biosynthetic class, polyketide, in particular, the nargenicin biosynthetic gene cluster from Nocardia argentinensis [
]. This family appears to be predominantly found in bacteria and unclassified phages.
This entry represents the ligand-binding domain found in ephrin type-A receptor 6 (EphA6). EphA6, like other Eph receptors and their ephrin ligands, seems to play a role in neural development, underlying learning and memory [
]. EphA6 has also been implicated in retinal vascular patterning [].Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands [
,
]. Ephrin receptors (EphRs) comprise the largest subfamily of receptor tyrosine kinases (RTKs). EphRs contain a ligand binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling) [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000376) is described by MIBiG as an example of the following biosynthetic class, NRP (non-ribosomal peptide), in particular JBIR-34 biosynthetic gene cluster from Streptomyces sp. Sp080513GE-23 [
]. This family appears to be predominantly found in actinobacteria.
Copper resistance protein CopA, second cupredoxin domain
Type:
Domain
Description:
CopA is a multicopper oxidase (MCO) related to laccase and L-ascorbate oxidase, both copper-containing enzymes [
,
]. CopA mutant causes a loss of function including copper tolerance and oxidase activity and copA transcription is inducible in the presence of copper [].Although MCOs have diverse functions, majority of them have three cupredoxin domain repeats that include one mononuclear and one trinuclear copper centre. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper centre and transferring them to the active site trinuclear copper centre. The cupredoxin domain 2 of 3-domain MCOs has lost the ability to bind copper [
,
,
,
].
This family of proteins is functionally uncharacterised. Proteins in this family are predominantly found in bacteria and have a conserved sequence motif GPV. Some members of this family are hypothetical ABC transporter permeases.
This entry represents the ligand-binding domain found in ephrin type-A receptor 7 (EphA7). EphA7 has been implicated in various cancers, including lung, prostate, as well as leukemia [
,
,
]. EphA7 has also been suggested to play a role in the development and maintenance of cortical domains within the cerebral cortex [].Class EphA receptors bind GPI-anchored ephrin-A ligands. There are ten vertebrate EphA receptors (EphA1-10), which display promiscuous interactions with six ephrin-A ligands [
,
]. Ephrin receptors (EphRs) comprise the largest subfamily of receptor tyrosine kinases (RTKs). EphRs contain a ligand binding domain and two fibronectin repeats extracellularly, a transmembrane segment, and a cytoplasmic tyrosine kinase domain. Binding of the ephrin ligand to EphR requires cell-cell contact since both are anchored to the plasma membrane. The resulting downstream signals occur bidirectionally in both EphR-expressing cells (forward signaling) and ephrin-expressing cells (reverse signaling) [
].
This entry represents a member of a biosynthetic gene cluster (BGC). This BGC (BGC0000187) is described by MIBiG as an example of the following biosynthetic class, polyketide, in particular the asukamycin biosynthetic gene cluster from Streptomyces nodosus subsp. asukaensis [
]. This family appears to be predominantly found in actinobacteria.
Copper resistance protein, first cupredoxin domain
Type:
Domain
Description:
CopA is a multicopper oxidase (MCO) related to laccase and L-ascorbate oxidase, both copper-containing enzymes [
,
]. CopA mutant causes a loss of function including copper tolerance and oxidase activity and copA transcription is inducible in the presence of copper [].Although MCOs have diverse functions, majority of them have three cupredoxin domain repeats that include one mononuclear and one trinuclear copper centre. The copper ions are bound in several sites: Type 1, Type 2, and/or Type 3. The ensemble of types 2 and 3 copper is called a trinuclear cluster. MCOs oxidize their substrate by accepting electrons at a mononuclear copper centre and transferring them to the active site trinuclear copper centre. The cupredoxin domain 1 of 3-domain MCOs contains part the trinuclear copper binding site, which is located at the interface of domains 1 and 3 [
,
,
,
].
