Type IV conjugative transfer system, coupling protein TraD
Type:
Family
Description:
The TraD protein performs an essential coupling function in conjugative type IV secretion systems. This protein sits at the inner membrane in contact with the assembled pilus and its scaffold as well as the relaxosome-plasmid DNA complex (through TraM) [
,
].
Type-F conjugative transfer system mating-pair stabilisation protein TraN
Type:
Family
Description:
TraN is a large cysteine-rich outer membrane protein involved in the mating-pair stabilisation (adhesin) component of the F-type conjugative plasmid transfer system. TraN is believed to interact with the core type IV secretion system apparatus through the TraV protein [,
,
].
Enhancer of mRNA-decapping protein 4, WD40 repeat region
Type:
Domain
Description:
This entry represents the N-terminal region of Ge-1, also known as EDC4 (enhancer of mRNA-decapping protein 4). This WD40-repeat region is involved in protein-protein interactions [
].
Resistance to inhibitors of cholinesterase protein 3, N-terminal
Type:
Domain
Description:
This entry represents the N-terminal domain of RIC3, a protein associated with nicotinic acetylcholine receptors (nAChRs), neurotransmitter-gated ion channels expressed at the neuromuscular junction and within the central and peripheral nervous systems [
,
]. It can enhance functional expression of multiple nAChR subtypes []. RIC3 promotes functional expression of homomeric alpha-7 and alpha-8 nicotinic acetylcholine receptors at the cell surface [].
Putative heme D1 biosynthesis radical SAM protein NirJ2
Type:
Family
Description:
Members of this radical SAM protein subfamily, designated NirJ2, occur in genomic contexts with a paralogue NirJ1 and with other nitrite reductase operon genes associated with heme D1 biosynthesis, as in Heliobacillus mobilis and Heliophilum fasciatum. NirJ2 is presumed by bioinformatics analysis [
] to be a heme D1 biosynthesis protein by context.
Mitogen-activated protein (MAP) kinase kinase kinase Ste11, Cryptococcus
Type:
Family
Description:
This group represents a MAP kinase kinase kinase (MAPKKK) STE11 from the jelly fungus Cryptococcus. It is similar to other fungal MAPKKK genes but is mating type specific [
].
Kelch-like protein 42, BTB and C-terminal Kelch domain
Type:
Domain
Description:
This entry represents the BTB and C-terminal Kelch domain found in KLHL42, which is a substrate-specific adaptor of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis. The BCR(KLHL42) E3 ubiquitin ligase complex mediates the ubiquitination and subsequent degradation of KATNA1. KLHL42 is involved in microtubule dynamics throughout mitosis [
].
Octopine catabolism/uptake operon regulatory protein OccR, PBP2 domain
Type:
Domain
Description:
This entry represents the C-terminal substrate-domain of OccR, which is a LysR-type transcriptional regulator of Agrobacterium tumefaciens that positively regulates the octopine catabolism operon of the Ti plasmid [
]. This substrate-binding domain shows significant homology to the type 2 periplasmic binding proteins (PBP2).The PBP2 are responsible for the uptake of a variety of substrates such as phosphate, sulfate, polysaccharides, lysine/arginine/ornithine, and histidine. The PBP2 bind their ligand in the cleft between these domains in a manner resembling a Venus flytrap. After binding their specific ligand with high affinity, they can interact with a cognate membrane transport complex comprised of two integral membrane domains and two cytoplasmically located ATPase domains. This interaction triggers the ligand translocation across the cytoplasmic membrane energized by ATP hydrolysis. Besides transport proteins, the PBP2 superfamily includes the substrate- binding domains from ionotropic glutamate receptors, LysR-like transcriptional regulators, and unorthodox sensor proteins involved in signal transduction [
,
,
].
Kinetochore null protein 2, Myb-like DNA-binding domain superfamily
Type:
Homologous_superfamily
Description:
This superfamily represents the Myb-like DNA-binding domain of Knl2 (kinetochore null protein 2) from C. elegans, a Myb DNA-binding domain-containing protein required for CENP-A loading and kinetochore assembly [
]. It has an all-helical structure.
Ribosomal protein L3, domain 3, archaeal type superfamily
Type:
Homologous_superfamily
Description:
This entry represents a domain found in L3 proteins from archaea and eukaryotes.
Ribosomal protein L3 is one of the proteins from the large ribosomal subunit. In Escherichia coli, L3 is known to bind to the 23S rRNA and may participate in the formation of the peptidyltransferase centre of the ribosome. It belongs to a family of ribosomal proteins which, on the basis of sequence similarities includes bacterial, red algal, cyanelle, mammalian, yeast and Arabidopsis thaliana L3 proteins; archaeal Haloarcula marismortui
HmaL3 (HL1), and yeast mitochondrial YmL9 [,
,
].
General transcription factor II-I repeat domain-containing protein 2
Type:
Family
Description:
This eukaryotic family includes general transcription factor II-I repeat domain-containing protein 2 (GTF2IRD2). The function of GTF2IRD2 is not clear.
Hepatitis C virus non-structural protein NS2, N-terminal domain
Type:
Homologous_superfamily
Description:
This superfamily represents the N-terminal domain of hepatitis C virus non-structural protein NS2.The viral genome is translated into a single polyprotein of about 3000 amino acids. Generation of the mature non-structural proteins relies on the activity of viral proteases. Non-structural protein 2 (NS2) is an zinc-dependent autocatalytic endopeptidase which cleaves at the NS2/NS3 junction [
,
]. The action of NS3 proteinase, which resides in the N-terminal one-third of the NS3 protein, then yields all remaining non-structural proteins.NS2 belongs to MEROPS peptidase family C18 (hepatitis C virus endopeptidase 2, clan CM). The fold consists of two subdomains connected by an extended linker: an N-terminal helical domain and a C-terminal beta sheet. Peptidases are active as a homodimer and the two active sites are formed at the dimer interface by His and Glu from one monomer and Cys from the other. The dimer resembles a 'butterfly' with two-fold symmetry along the vertical axis. The N-terminal subdomain of one molecule interacts with the C-terminal subdomain of the other molecule and vice versa [
].
Hepatitis C virus non-structural protein NS2, C-terminal domain
Type:
Homologous_superfamily
Description:
This superfamily represents the C-terminal domain of hepatitis C virus non-structural protein NS2.The viral genome is translated into a single polyprotein of about 3000 amino acids. Generation of the mature non-structural proteins relies on the activity of viral proteases. Non-structural protein 2 (NS2) is an zinc-dependent autocatalytic endopeptidase which cleaves at the NS2/NS3 junction [
,
]. The action of NS3 proteinase, which resides in the N-terminal one-third of the NS3 protein, then yields all remaining non-structural proteins.NS2 belongs to MEROPS peptidase family C18 (hepatitis C virus endopeptidase 2, clan CM). The fold consists of two subdomains connected by an extended linker: an N-terminal helical domain and a C-terminal beta sheet. Peptidases are active as a homodimer and the two active sites are formed at the dimer interface by His and Glu from one monomer and Cys from the other. The dimer resembles a 'butterfly' with two-fold symmetry along the vertical axis. The N-terminal subdomain of one molecule interacts with the C-terminal subdomain of the other molecule and vice versa [].
Enhancer of mRNA-decapping protein 4, conserved C-terminal domain
Type:
Homologous_superfamily
Description:
This superfamily represents the highly conserved C-terminal region of Enhancer of mRNA-decapping protein 4 (EDC4, also known as Ge-1) which adopts an all α-helical fold [
,
]. This domain is necessary and sufficient for P-body targeting and, in plants, it also mediates DCP1 and DCP2 interaction, as well as self-association [].
Tomato bushy stunt virus (TBSV), p22, movement protein
Type:
Family
Description:
Two small nested genes (p19 and p22) are located near the 3' end of the genome of tomato bushystunt virus (TBSV) - the p19 gene encodes a soluble protein, whereas the p22 gene specifies a membrane-associated protein. p22 is required for cell-to-cell movement in all plants tested [
].
ABC transporter, high-affinity heme uptake system protein IsdE
Type:
Family
Description:
This family of ABC substrate-binding proteins is observed primarily in close proximity with proteins localised to the cell wall and bearing the NEAT (NEAr Transporter,
) haem-binding domain [
,
]. IsdE has been shown to bind heme and is involved in the process of scavenging haem for the purpose of obtaining iron [,
].
Maltose transport system permease protein MalF, P2 domain
Type:
Domain
Description:
The maltose transport system is composed of a periplasmic maltose-binding protein (MBP), two integral membrane proteins, MalF and MalG, and two copies of the cytoplasmic ATP-binding cassette MalK [
]. The structures of the two transmembrane (TM) subunits, MalF and MalG, are composed of eight and six TM helices, respectively. The TM helices of MalF and MalG assemble into two crescent shaped structures with their concave surfaces facing each other and enclosing the maltose. MalF consists of four periplasmic domains. This entry represents the second periplasmic loop of MalF (P2), which binds to MalE and is involved in activation of the MalFGK2-E complex by inducing structural changes in maltose-bound MalE []. P2 is also responsible for substrate recognition [,
,
].
LIM and senescent cell antigen-like-containing domain protein 1-4-like
Type:
Family
Description:
This group represents LIM and senescent cell antigen-like-containing domain protein 1 (LIMS1, also known as PINCH-1), and its homologues LIMS2-4, LIM domain-containing protein unc-97 and LIM domain-containing protein pin-2. LIMS1 is LIM domain adapter protein that functions in the integrin and growth factor signal transduction pathway [
]. Unc-97 is part of the integrin containing attachment complex, which is required for muscle development and maintenance []; it may also function in adherens junction [].
Chitin synthesis regulation, Congo red resistance, RCR protein
Type:
Family
Description:
RCR proteins are ER membrane proteins that regulate chitin deposition in fungal cell walls. Although chitin, a linear polymer of beta-1,4-linked N-acetylglucosamine, constitutes only 2% of the cell wall it plays a vital role in the overall protection of the cell wall against stress, noxious chemicals and osmotic pressure changes. Congo red is a cell wall-disrupting benzidine-type dye extensively used in many cell wall mutant studies that specifically targets chitin in yeast cells and inhibits growth. RCR proteins render the yeasts resistant to Congo red by diminishing the content of chitin in the cell wall []. RCR proteins are probably regulating chitin synthase III interact directly with ubiquitin ligase Rsp5, and the VPEY motif is necessary for this, via interaction with the WW domains of Rsp5 [].
Non-structural protein NSP3, nucleic acid-binding domain superfamily, betacoronavirus
Type:
Homologous_superfamily
Description:
This superfamily represents the the nucleic acid binding domain (NAB/NAR) domain, which is approximately 100 residues in length, found in the multidomain nonstructural protein NSP3 from betacoronavirus, and described as NSP3e domain. NSP3 is part of Orf1a polyproteins in SARS-CoV [
]. It is an essential component of the replication/transcription complex [].The global domain of the NAB represents a new fold, with a parallel four-strand β-sheet holding two α-helices of three and four turns that are oriented antiparallel to the β-strands. A group of residues form a positively charged patch on the protein surface as the binding site responsible for binding affinity for nucleic acids. When binding to ssRNA, the NAB prefers sequences with repeats of three consecutive Gs, such as (GGGA)5 and (GGGA)2. A positively charged surface patch (Lys75, Lys76, Lys99, and Arg106) is involved in RNA binding [
,
,
].
KAT8 regulatory NSL complex subunit 3/Testis-expressed sequence 30 protein
Type:
Family
Description:
This entry includes the animal KAT8 regulatory NSL complex subunit 3 (KANSL3 or NSL3, also known as testis development protein PRTD), the testis-expressed sequence 30 proteins and their homologues, such as C. elegans SUMV-2 protein.KAT8 regulatory NSL complex subunit 3 is part of the NSL complex that is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription [
]. The function of the testis-expressed sequence 30 protein is not known.SUMV-2 interacts with SUMV-1, and they may function together with MYS-2 in a nematode KAT8/MOF-like complex to antagonise the activity of the synMuv (synthetic multivulva) genes [
]. This entry also includes uncharacterized bacterial proteins.
Para-hydroxybenzoic acid efflux pump subunit AaeB/fusaric acid resistance protein
Type:
Family
Description:
This entry represents the p-hydroxybenzoic acid efflux pump subunit AaeB (pHBA efflux pump protein B) whose substrates are p-hydroxybenzoic acid (pHBA), 6-hydroxy-2-naphthoic and 2-hydroxycinnamate. It could function as a metabolic relief valve, allowing to eliminate certain compounds when they accumulate to high levels in the cell [
]. This family also includes fusaric acid resistance proteins [], which are likely to be membrane transporter proteins, and uncharacterised transporter YdhK.
Domain of unknown function DUF3385, target of rapamycin protein
Type:
Domain
Description:
This uncharacterised domain is is typically between 160 to 172 amino acids in length. It is found in the phosphatidylinositol kinase-related protein kinases TOR (target of rapamycin). In Saccharomyces cerevisiae the TOR proteins, TOR1 and TOR2, regulate growth in a rapamycin-sensitive manner [
].
Heat shock protein Hsp33, helix hairpin bin domain superfamily
Type:
Homologous_superfamily
Description:
Hsp33 is a molecular chaperone, distinguished from all other known chaperones by its mode of functional regulation. Its activity is redox regulated. Hsp33 is a cytoplasmically localized protein with highly reactive cysteines that respond quickly to changes in the redox environment. Oxidizing conditions like H
2O
2cause disulphide bonds to form in Hsp33, a process that leads to the activation of its chaperone function. In normal (reducing) cytosolic conditions, four conserved Cys residues are coordinated by a Zn ion. Hsp33 is homodimeric in its functional form [,
,
,
].This superfamily represents a helix hairpin bin domain found in Hsp33. This domain folds into three helices that pack on the other subunit of the Hsp33 dimer [
].
Kelch repeat and BTB domain-containing protein 8, BTB/POZ domain
Type:
Domain
Description:
The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs [
].Kelch repeat and BTB domain-containing protein 8 (KBTBD8) belongs to the BTB-kelch protein family. KBTBD8 localises in the Golgi apparatus and translocates to the spindle apparatus during mitosis [
]. It acts as a substrate-specific adaptor of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of neural crest specification. The BCR(KBTBD8) complex monoubiquitylates NOLC1 and its paralog TCOF1, the mutation of which underlies the neurocristopathy Treacher Collins syndrome []. This entry represents the BTB/POZ domain.
Type-F conjugative transfer system pilin assembly protein TrbC, subgroup
Type:
Family
Description:
This entry represents TrbC, a protein that is an essential component of the F-type conjugative pilus assembly system (aka type 4 secretion system) for the transfer of plasmid DNA [
,
]. The N-terminal portion of these proteins is heterogeneous.
FERM and PDZ domain-containing protein 1/3/4, FERM domain C-lobe
Type:
Domain
Description:
FRMPD1, FRMPD3, and FRMPD4 contain an N-terminal PDZ domain and a C-terminal FERM domain. The PDZ domain helps anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes. The PDZ domain also binds to a short region of the C terminus of other specific proteins. The FERM domain is composed of three subdomains: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), which form a clover leaf fold. The C-lobe/F3 within the FERM domain is part of the PH domain superfamily. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites [
,
].This entry represents the C-lobe of the FERM domain found in FRMPD1/3/4. FRMPD1 regulates the subcellular location of activator of G-protein signaling 3 and its interaction with G-proteins []. FRMPD4 has been shown to regulates dendritic spine morphogenesis []. The function of FRMPD3 is not clear.
Elongation of very long chain fatty acids protein 7
Type:
Family
Description:
Elongation of very long chain fatty acids protein 7 (ELOVL7) is an enzyme of the long-chain fatty acid elongation cycle. It is a transmembrane protein found in the endoplasmic reticulum with the active site within one of the transmembrane regions. ELOVL7 adds two carbons per cycle to the chains of long and very long fatty acids with higher activity towards C18 acyl-CoAs. ELOVL7 has been implicated in prostate cancer growth and the gene is regulated by the androgen pathway through SREBP1 [
].
Elongation of very long chain fatty acids protein 6
Type:
Family
Description:
Elongation of very long chain fatty acids protein 6 (ELOVL6) is a membrane-bound enzyme located in the endoplasmic reticulum that is component of the long-chain fatty acids elongation cycle. ELOVL6 adds two carbons per cycle to long- and very long-chain fatty acids with a preference for 12, 14 and 16 carbons with higher activity toward C16:0 acyl-CoAs [
].
Elongation of very long chain fatty acids protein 5
Type:
Family
Description:
Elongation of very long chain fatty acids protein 5 (ELOVL5) is a component of the the long-chain fatty acids elongation cycle. It is a transmembrane enzyme in the endoplasmic reticulum that adds two carbons per cycle to long- and very long-chain fatty acids with a preference for polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA [
].
Elongation of very long chain fatty acids protein 4
Type:
Family
Description:
Elongation of very long chain fatty acids protein 4 (ELOVL4) is a component of the the long-chain fatty acids elongation cycle. It is a transmembrane enzyme in the endoplasmic reticulum that adds two carbons per cycle to long- and very long-chain fatty acids with a preference for elongating C24:0 and C26:0 acyl-CoAs [
].
Elongation of very long chain fatty acids protein 3
Type:
Family
Description:
Elongation of very long chain fatty acids protein 3 (ELOVL3) is a component of the the long-chain fatty acids elongation cycle. It is a transmembrane enzyme in the endoplasmic reticulum that adds two carbons per cycle to long- and very long-chain fatty acids with a higher activity toward C18 acyl-CoAs, especially C18:0 acyl-CoAs [
].
Elongation of very long chain fatty acids protein 2
Type:
Family
Description:
Elongation of very long chain fatty acids protein 2 (ELOVL2) is a component of the the long-chain fatty acids elongation cycle. It is a transmembrane enzyme in the endoplasmic reticulum that adds two carbons per cycle to long- and very long-chain fatty acids actng on polyunsaturated acyl-CoA with the higher activity toward C20:4(n-6) acyl-CoA [
].
Elongation of very long chain fatty acids protein 1
Type:
Family
Description:
Elongation of very long chain fatty acids protein 1 (ELOVL1) is a component of the the long-chain fatty acids elongation cycle. It is a transmembrane enzyme in the endoplasmic reticulum that adds two carbons per cycle to long- and very long-chain fatty acids with a preference for condensing saturated C18 to C26 acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA [
].
Polycomb group RING finger protein 6, C3HC4-type RING finger
Type:
Domain
Description:
Polycomb group RING finger protein 6 (PCGF6 or MBLR) is a transcriptional repressor []. It may activate KDM5D histone demethylase, which modulates the levels of histone H3K4Me3 []. PCGF6 is a component of the Polycomb group (PcG) multiprotein PRC1-like complex [], in which it regulates RNF2 ubiquitin ligase activity [], and the E2F6.com-1 complex []. PCGF6 contains a RING-type zinc finger.This entry represents the C3HC4-type RING-HC finger of PCGF6.
AT-rich interactive domain-containing protein 4B, ARID/BRIGHT DNA binding domain
Type:
Domain
Description:
AT-rich interactive domain-containing protein 4B (ARID4B) acts as a transcriptional repressor. It may function in the assembly and/or enzymatic activity of the Sin3A corepressor complex or in mediating interactions between the complex and other regulatory complexes [
]. It may play an integral part in the AR (androgen receptor) and RB (retinoblastoma) regulatory pathways involved in the regulation of Sertoli cell function and male fertility []. It is linked to tumor growth and metastasis [].This entry represents the AT-rich ARID/BRIGHT DNA binding domain of ARID4B.
Protein disulfide-isomerase A3, first redox inactive TRX-like domain b
Type:
Domain
Description:
This entry represents the first redox inactive TRX-like domain b found in protein disulfide-isomerase A3 (also known as ERp57). ERp57 exhibits both disulfide oxidase and reductase functions like PDI, by catalyzing the formation of disulfide bonds of newly synthesized polypeptides in the ER and acting as isomerases to correct any non-native disulfide bonds [
]. It also displays chaperone activity to prevent protein aggregation and facilitate the folding of newly synthesized proteins. ERp57 contains two redox-active TRX (a) domains and two redox inactive TRX-like (b) domains. It shares the same domain arrangement of abb'a' as PDI, but lacks the C-terminal acid-rich region (c domain) that is present in PDI [,
]. ERp57 interacts with the lectin chaperones, calnexin and calreticulin, and specifically promotes the oxidative folding of glycoproteins [,
,
]. Similar to PDI, the b domain of ERp57 is likely involved in binding to substrates [].
Uncharacterised conserved protein UCP036888, signal transduction HD-GYP-like, PA5346 type
Type:
Family
Description:
Members of this group contain a modified version of the HD-GYP domain and an uncharacterised N-terminal domain. There is currently no experimental data for members of this group.HD-GYP is a conserved domain found in response regulator modules of various signal transduction systems. The involvement of the HD-GYP domain in signal transduction was originally proposed on the basis of its association with CheY-like and other signal transduction domains [
] and was later directly demonstrated experimentally by showing that RpfG is involved in regulation of the biosynthesis of extracellular endoglucanase and polysaccharide [].A modification of the HD-GYP domain, which is found in this group,
, and several smaller groups, lacks the conserved distal portion of the domain and has certain substitutions in the characteristic metal-binding residues [
] of the HD superfamily phosphohydrolases, which likely render it catalytically inactive. Note that the prototypical HD domain () is not recognised in many members of this group.
The exact mode of action and targets of the HD-GYP output domain are not known [
]. HD-GYP proteins are associated to the HD domain superfamily of metal-dependent phosphohydrolases; HD designates the principal conserved residues implicated in metal binding and catalysis []. The HD-GYP version of the HD-type domain has many additional highly conserved residues, including a conserved GYP motif, hence its name [,
].It has been noted that the highly conserved sequence of the HD-GYP domain suggests high substrate specificity [
]. On the basis of its association with the GGDEF diguanylate cyclase domain, it has been also predicted that the HD-GYP domain may be involved in the metabolism of cyclic diguanylate or in dephosphorylation of some phosphotransfer domain [].
Tripartite motif-containing protein 66, B-box type 1 zinc finger
Type:
Domain
Description:
Tripartite motif-containing protein 66 (TRIM66, also known as transcriptional intermediary factor 1 delta, TIF1delta) binds to HP1 (heterochromatin protein 1) and is expressed by elongating spermatids. It displays a potent trichostatin A (TSA)-sensitive repression function; TSA is a specific inhibitor of histone deacetylases. Moreover, TRIM66 plays an important role in heterochromatin-mediated gene silencing during postmeiotic phases of spermatogenesis [
]. It functions as a negative regulator of postmeiotic genes acting through HP1 isotype gamma (HP1gamma) complex formation and centromere association. TRIM66 belongs to an unclassified TRIM (tripartite motif) family of proteins that do not have RING fingers and thus lack the characteristic tripartite (RING (R), B-box, and coiled coil (CC)) RBCC motif. This entry represents the type 1 B-box (Bbox1) zinc finger which is characterised by a C6H2 zinc-binding consensus motif [
,
].
Protein phosphatase Slingshot homologue 1, dual specificity phosphatase domain
Type:
Domain
Description:
Slingshot homologue 1 (SSH1) is a dual specificity protein phosphatase which regulates actin filament dynamics. It dephosphorylates and activates the actin binding/depolymerising factor cofilin, which subsequently binds to actin filaments and stimulates their disassembly [
,
,
]. SSH1 links NOD1 signaling to actin remodeling, facilitating the changes that leads to NF-kappaB activation and innate immune responses [,
,
,
]. There are at least two human SSH1 isoforms reported: hSSH-1L (long) and hSSH-1S (short). As SSH family phosphatases, they contain an N-terminal, SSH family-specific non-catalytic (SSH-N) domain, followed by a short domain with similarity to the C-terminal domain of the chromatin-associated protein DEK, and a dual specificity phosphatase catalytic domain. They also contain C-terminal tails, differing in the lengths of the tail. This entry represents the dual specificity phosphatase domain (DSP) of SSH1.
Zinc finger and BTB domain-containing protein 40, BTB/POZ domain
Type:
Domain
Description:
The function of Zinc finger and BTB domain-containing protein 40 (ZBTB40) is not clear. It has been linked to the reduced hip bone mineral density (BMD) and the increased risk of hip osteoporosis [
,
].This entry represents the N-terminal BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain of ZBTB40.
Kelch repeat and BTB domain-containing protein 2, BTB/POZ domain
Type:
Domain
Description:
KBTBD2, also called BTB and kelch domain-containing protein 1 (BKLHD1), plays an essential role in the regulation of insulin-signaling pathway. It is a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase, which targets p85alpha, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85alpha ubiquitination and proteasome-mediated degradation. This entry represents the BTB/POZ domain [
,
].The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs [
].
Kelch repeat and BTB domain-containing protein 3, BTB/POZ domain
Type:
Domain
Description:
This entry represents the BTB/POZ domain of Kelch repeat and BTB domain-containing protein 3 (KBTBD3), whose function is not clear.The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs [
].
Structural maintenance of chromosomes flexible hinge domain-containing protein 1
Type:
Family
Description:
SMCHD1 plays roles in X-chromosome inactivation, imprinting and double-strand break repair. Mutations in the SMCHD1 gene have been linked to Facioscapulohumeral dystrophy. Its N-terminal half contains a GHKL (gyrase, Hsp90, histidine kinase, MutL) ATPase motif, whereas its C terminus contains an SMC (structural maintenance of chromosomes) domain homologous to that found in cohesins and condensins, which has DNA-binding activity and provides an interface for homodimerization [
].
Dual specificity mitogen-activated protein kinase kinase 5, PB1 domain
Type:
Domain
Description:
Mitogen-activated protein kinase kinase 5 (MAP2K5, alias MEK5) is a member of the ERK5 pathway, involved in angiogenesis and development [
,
]. ERK5 is a MAPK activated in response to various stimuli through a three-tier cascade constituting MEK5 and MEKK2/3. MEK5 phosphorylates the activation loop of ERK5 at Thr218 and Tyr220 leading to its activation []. The PB1 domain of MEK5 interacts with the PB1 domains of other members of the kinase cascade, MEKK2 and MEKK3 [].The PB1s are dimerization/oligomerization domains present in adaptor and scaffold proteins as well as kinases and serve to organize platforms that ensure specificity and fidelity during cellular signalling [
]. The interaction between two PB1 domain depends on the type of PB1. There are three types of PB1 domains: type I which contains an OPCA motif, acidic aminoacid cluster, type II which contains a basic cluster, and type I/II which contains both an OPCA motif and a basic cluster. The Map2k5 protein contains a type I PB1 domain [].
WD repeat-containing and planar cell polarity effector protein Fritz
Type:
Family
Description:
Fritz is a probable effector of the planar cell polarity signaling pathway which regulates the septin cytoskeleton in both ciliogenesis and collective cell movements. In Drosophila melanogaster, fritz regulates both the location and the number of wing cell prehair initiation sites [
].
Nuclear pore complex protein Nup98-Nup96-like, autopeptidase S59 domain superfamily
Type:
Homologous_superfamily
Description:
Nuclear pore complexes (NPCs) facilitate all nucleocytoplasmic transport in eukaryotic cells, playing essential roles in cellular homeostasis. The NPC is a modular structure composed of multiple copies of ~30 proteins (nucleoporins, Nups) arranged into distinct subcomplexes [
,
]. A number of these peptides are synthesised as precursors and undergo self-catalyzed cleavage. The largest NPC sub-complex is the heptameric Y-shaped mammalian Nup107-Nup160 complex (called Nup84 complex in budding yeast), an essential scaffolding component of the NPC [,
,
]. Nup98 and Nup96 are encoded by the same gene that produces a 190 kDa polyprotein with autoproteolytic activity which generates the N-terminal NUP98 and C-terminal NUP96 proteins, part of the Nup107-Nup160 subcomplex [
,
]. The yeast homologue Nup145 undergoes the similar proteolytic event to produce Nup145N and Nup145C, which are part of the Nup84 complex. The function of the heptamer is to coat the curvature of the nuclear pore complex between the inner and outer nuclear membranes. Nup96, which is predicted to be an alpha helical solenoid, complexes with Sec13 in the middle of the heptamer. The interaction between Nup96 and Sec13 is the point of curvature in the heptameric complex [,
].The proteolytic cleavage site of yeast Nup145p has been mapped upstream of an evolutionary conserved serine residue. Then, Nup145C form the heptameric Y-complex together with six other proteins while Nup145N shuttle between the NPC and the nuclear interior. [
,
].Nup98, a component of the nuclear pore that plays its primary role in the export of RNAs, is expressed in two forms, derived from alternate mRNA splicing. Both forms are processed into two peptides through autoproteolysis mediated by the C-terminal domain of hNup98. The three-dimensional structure of the C-terminal domain reveals a novel protein fold, and thus a new class of autocatalytic proteases. The structure further reveals that the suggested nucleoporin RNA binding motif is unlikely to bind to RNA [
].The following nucleoporins share an ~150-residue C-terminal domain responsible for NPC targeting [
,
]:Vertebrate Nup98, a component of the nuclear pore that plays its primary role in the export of RNAs.
Yeast Nup100, plays an important role in several nuclear export and import pathways including poly(A)+ RNA and protein transport.
Yeast Nup116, involved in mRNA export and protein transport.
Yeast Nup145, involved in nuclear poly(A)+ RNA and tRNA export.The NUP C-terminal domains of Nup98 and Nup145 possess peptidase S59
autoproteolytic activity. The autoproteolytic sites of Nup98 and Nup145each occur immediately C-terminal to the NUP C-terminal domain. Thus, although
this domain occurs in the middle of each precursor polypeptide, it winds up atthe C-terminal end of the N-terminal cleavage product. Cleavage of the peptide
chains are necessary for the proper targeting to the nuclear pore [,
].The NUP C-terminal domain adopts a predominantly β-strand structure. The molecule consists of a six-stranded β-sheet sandwiched against a two-stranded β-sheet and flanked by α-helical regions. The N-terminal helical region consists of two short helices, whereas the stretch on the opposite side of molecule consists of a single, longer helix [
,
].
Interferon regulatory factor 2-binding protein 1 &2, zinc finger
Type:
Domain
Description:
Interferon regulatory factor 2-binding protein 1 and 2 (IRF-2BP1/2) and their homologue IRF-2BP-like (also known as IRF-2BPL or C14orf4) () are nuclear transcriptional repressor proteins that bind to the C-terminal repression domain of IRF-2 and can inhibit both enhancer-activated and basal transcription. They contain N-terminal zinc finger and C-terminal RING finger domains [
,
,
]. Mutations in IRF2BP2 are responsible for a Familial Form of Common Variable Immunodeficiency Disorder (CVID), one of the most frequently diagnosed forms of primary immunodeficiency characterised by low quantity of IgG and IgA and poor specific antibody production []. IRF2BPL may play a role in the development of the central nervous system and in neuronal maintenance [].This entry represents the N-terminal zinc finger domain of IRF-2BP1 and IRF-2BP2.
Regulator of G protein signaling 14, Ras-binding domain 2
Type:
Domain
Description:
RGS14 is a regulator of G protein signaling (RGS) protein and contains an N-terminal RGS domain, two tandem Ras-binding domains (RBDs) and a G protein regulatory (GPR, also referred to as a GoLoco) motif. It regulates G protein nucleotide exchange and hydrolysis by acting as a GTPase-activating protein (GAP) through its RGS domain, and as a guanine nucleotide dissociation inhibitor (GDI) through its GoLoco motif [
,
]. Both domains of RGS14 target members of the Gialpha subclass []. It is a microtubule-associated protein that may modulate microtubule dynamics and spindle formation [] and play an essential role during mammalian cell division []. RGS14 regulates the activation of alphaMbeta2 integrin during phagocytosis []. It is a key regulator of signalling pathways linking synaptic plasticity in CA2 pyramidal neurons to hippocampal-based learning and memory [].RGS14 binds activated H-Ras-GTP through its first RBD and interacts with Rap2-GTP and RAF kinases by the second tandem RBD. This entry represents the second RBD. RBD is structurally similar to the β-grasp fold of ubiquitin, a common structure involved in protein-protein interactions. RGS14 modulates neuronal physiology and all of its binding partners have roles in synaptic plasticity [,
,
,
,
].
Cation efflux system protein CusB, long alpha hairpin domain
Type:
Domain
Description:
This entry represents the long alpha-hairpin domain found in the centre of CusB or HlyD proteins. CusB and HlyD proteins are membrane fusion proteins of the CusCFBA copper efflux system in E.coli and related bacteria. Efflux systems of this resistance-nodulation-division group - RND - have been developed to excrete poisonous metal ions, and in E.coli the only one that deals with silver and copper is the CusA transporter. The transporter CusA works in conjunction with a periplasmic component that is a membrane fusion protein, eg CusB, and an outer-membrane channel component CusC in a CusABC complex driven by import of protons. This domain is thought to interact with the α-helical tunnels of the corresponding outer-membrane channels, ie the periplasmic domain of CusC [
].
Small protein from certain CxC ATPase-based DNA modification systems
Type:
Family
Description:
This entry represents a small protein, that, analogous to an antitoxin, it potentially acts as a negative regulatory component that might sense the presence of invaders by acting as a binding factor or substrate for invader-encoded enzymes like viral peptidases in certain CxC ABC ATPase-based DNA modification systems [
].
Small protein found in certain Dnd DNA modification systems
Type:
Family
Description:
This entry represents a small protein found in bacteria, that, analogous to an antitoxin, it potentially acts as a negative regulatory component that might sense the presence of invaders by acting as a binding factor or substrate for invader-encoded enzymes like viral peptidases in certain Dnd systems [
]. In some members included in this entry the model represents a domain associated with .
F-BAR and double SH3 domains protein 2, F-BAR domain
Type:
Domain
Description:
F-BAR proteins have been identified as important coordinators for membrane curvatures, which regulate cellular processes such as endocytosis, phagocytosis, adhesion and migration [
]. They bind to cell membrane via a N-terminal F-BAR domain, which associates with membrane phospholipids []. F-BAR and double SH3 domains protein 2 (FCHSD2), also known as carom, contains an N-terminal F-BAR domain and two SH3 domains at the C terminus []. It may mediate receptor endocytosis and transport [].This entry represents the N-terminal F-BAR (FES-CIP4 Homology and Bin/Amphiphysin/Rvs) domain of FCHSD2.
Flagellum site-determining protein YlxH/ Fe-S cluster assembling factor NBP35
Type:
Family
Description:
This family contains YlxH (also annotated FleN/FlhG), which regules aspects of flagellar assembly, placement and number [
,
]. YlxH/FlhG activates the SRP-GTPase FlhF []. This family also contains members of the MRP/Nbp35 class of iron-sulfur (FeS) cluster scaffolds, such as Nbp35 and Cfd1, that function to assemble nascent FeS clusters for transfer to FeS-requiring enzymes. They have been identified as ATPases [].
Aerobic respiration control sensor protein ArcB, transmembrane domain superfamily
Type:
Homologous_superfamily
Description:
Histidine kinase receptors (HKR) are part of a two-component system, in which an HKR in the bacterial inner membrane transmits a signal to a response regulator located in the cytoplasm.Escherichia coli sensor kinase ArcB phosphorylates the partner response regulator ArcA in response to anaerobic conditions [
]. ArcB is an atypical sensor kinase containing multiple phosphorylation domains: a histidine-containing phosphotransfer (HPt) signaling domain and a receiver domain in addition to the receptor and histidine-kinase (transmitter) domains, which are the two domains constituting a typical sensor kinase [,
].ArcB is a class 2 histidine kinase receptor (HKR). Class 2 HKRs lack an apparent extracytoplasmic domain and the stimuli-sensing region is believed to be in the membrane domain itself. ArcB has two transmembrane (TM) helices connected by a short periplasmic loop. This superfamily represents this transmembrane domain consisting of two helical motifs [
].
Amyloid beta precursor protein binding family B member 1/2/3
Type:
Family
Description:
This entry represents the FE65 family, whose members include FE65 (APBB1), FE65L1 (APBB2), and FE65L2 (APBB3). They are adaptor proteins that bind the C-terminal region of the amyloid precursor protein (APP) [
]. APBB1 is a neuronal adaptor protein involved in brain development, Alzheimer disease amyloid precursor protein (APP) signaling, and proteolytic processing of APP [
,
]. It contains three protein-protein interaction domains, one WW domain, and two phosphotyrosine-binding domains (PTBs)[]. The C-terminal Fe65-PTB2 binds a large portion of the APP intracellular domain (AICD) including the GYENPTY internalization sequence fingerprint []. This entry also includes an Fe65 homologue from C. elegans, Feh-1. Besides binding to amyloid precursor protein, it is also involved in the same pathway that controls nematode pharyngeal pumping [
].
Altered inheritance of mitochondria protein 6, PI-PLC-like catalytic domain
Type:
Domain
Description:
This entry represents the PI-PLC (phosphoinositide-specific phospholipase C) -like catalytic domain found in baker's yeast Aim6 (altered inheritance of mitochondria protein 6) and related proteins. The function of Aim6 is not clear.
RING finger and SPRY domain-containing protein 1, SPRY domain
Type:
Domain
Description:
This SPRY domain is found at the N terminus of RING finger domains which are present in a variety of functionally distinct proteins and are known to be involved in protein-protein and protein-DNA interactions. The RING-finger domain is a type of Zn-finger that binds two Zn atoms.The role of RSPRY1 (RING finger and SPRY domain-containing protein 1) is not known, but it may have a role in bone development. Mutations in RSPRY1 cause skeletal dysplasia [
].
Ankyrin repeat and LEM domain-containing protein 2, LEM domain
Type:
Domain
Description:
Lem4 (also called ANKLE2) and C. elegans orthologue LEM-4L are required for BAF dephosphorylation. Lem4 coordinates BAF dephosphorylation by inhibiting kinase VRK-1 and by supporting PP2A dephosphorylation of BAF during mitotic exit [
].Barrier-to-autointegration factor (BAF) is an essential protein that binds to dsDNA, chromatin, nuclear lamina proteins, histones and various transcription factors [
]. Members of the vaccinia-related kinase (VRK) family of mitotic kinases phosphorylate BAF in mitosis and meiosis; this modification strongly reduces the affinity of BAF for chromatin and slightly weakens its affinity for LEM proteins. BAF dephosphorylation has been linked to mitotic exit and postmitotic NE formation [].ANKLE2 contains an N-terminal LEM domain and an ankyrin repeat region. The LEM domain is known to interact with BAF []. The ankyrin repeats are unique motifs mediating protein-protein interactions.This entry represents the LEM domain.
Bromodomain adjacent to zinc finger domain protein 1A, bromodomain
Type:
Domain
Description:
Bromo adjacent to zinc finger 1A (also known as ACF1) is the regulatory subunit of the ACF-1 and ACF-5 ISWI chromatin remodeling complexes,
which form ordered nucleosome arrays on chromatin and regulates spacing of nucleosomes using ATP to generate evenly spaced nucleosomes along the chromatin [,
,
,
]. Bromodomains are 110 amino acid long domains, that are found in many chromatin associated proteins. Bromodomains can interact specifically with acetylated lysine [,
].
Elongin BC and Polycomb repressive complex 2-associated protein EPOP
Type:
Family
Description:
In mouse embryonic stem cells (mESCs), the transcriptional network can be divided into three functionally distinct modules: Polycomb, Core, and Myc, and the Polycomb module represses developmental genes [
]. This family includes the polycomb repressive complex 2-associated factor EPOP (Elongin BC and Polycomb Repressive Complex 2 (PRC2) Associated Protein, also termed C17orf96, esPRC2p48, E130012A19Rik), a scaffold protein expressed in the inner cell mass of the mouse blastocyst serving as a bridging partner between the PRC2/EED-EZH2 complex and the elongin BC complex, and fine-tuning the transcriptional status of Polycomb group (PcG) target genes in embryonic stem cells. Both EPOP and Elongin BC are required to maintain low levels of expression at PRC2 genomic targets []. EPOP interacts with the H2B deubiquitinase USP7 to modulate transcriptional processes in mESCs similar to MYC [].Another member of the family is the uncharacterized SKI/DACH domain-containing protein 1.
Scm-like with four MBT domains protein 1/2, SAM domain
Type:
Domain
Description:
Scm-like-4MBT1 and Scm-like-4MBT2 are structurally related to the transcriptional repressor Polycomb group (PcG) proteins. They contain a SAM domain, a SLED domain [
], and four MBT repeats []. The MBT repeats of the human SFMBT1 protein are responsible for association with the nuclear matrix and for selective binding of H3 histone N-terminal tails []. SFMBT1 also forms a stable complex with LSD1 and CoREST that causes chromatin compaction and transcriptional repression of target genes, including those encoding replication-dependent histones [].This entry represents the SAM domain of Scm-like-4MBT1/2.
Ankyrin repeat and SAM domain-containing protein 3, SAM domain
Type:
Domain
Description:
This entry represents the SAM (sterile alpha motif) domain of ANKS3. This domain, which is located in the C-terminal region, is typical of signalling proteins.This group of proteins includes Ankyrin repeat and SAM domain-containing protein 3 (ANKS3), which may be involved in vasopressin signalling in the kidney [].
Sporulation stage II protein D, amidase enhancer LytB N-terminal
Type:
Domain
Description:
This domain is found in the stage II sporulation protein SpoIID. SpoIID is necessary for membrane migration as well as for some of the earlier steps in engulfment during bacterial endospore formation [
]. The domain is also found in amidase enhancer proteins. Amidases, like SpoIID, are cell wall hydrolases [].
Gap junction alpha-1 protein (Cx43), alpha helix domain superfamily
Type:
Homologous_superfamily
Description:
Gap junction alpha-1 protein (also called connexin43, or Cx43) is a connexin
of 381 amino acid residues (human isoform) that is widely expressed inseveral organs and cell types, and is the principal gap junction protein of
the heart. Characterisation of genetically-engineered mice that lack Cx43,and also of human patients that have spontaneously-occurring mutations in
the gene encoding it (GJA1), suggest Cx43 is essential for the developmentof normal cardiac architecture and ventricular conduction. Mice lacking Cx43
survive to term but die shortly after birth. They have cardiac malformationsthat lead to the obstruction of the pulmonary artery, leading to neonatal
cyanosis, and subsequent death. This phenotype is reminiscent of some formsof stenosis of the pulmonary artery. Human subjects with visceroatrial
heterotaxia (a heart disorder characterised by arterial defects), have beenfound to have points mutations in the Cx43-encoding gene, as a result of
which a potential phosphorylation site within the C terminus is disrupted. Consequently, although these mutant Cx43 molecules still form functional gap
junction channels, their response to protein kinase activation is impaired.Regulation of cell-cell communication by the gap junction protein connexin43 can be modulated by a variety of connexin-associating proteins. In particular, c-Src can disrupt the connexin43 (Cx43)-zonula occludens-1 (ZO-1) interaction, leading to down-regulation of gap junction intercellular communication. The connexin43 carboxyl-terminal domain (Cx43CT) exists primarily as an elongated random coil, with two regions of α-helical structure.
The α-helical domains has two hypothetical roles. The first one is to allow the formation of a higher order structure necessary to regulate channel behavior during chemical gating and the second is to act as a conduit for a cross-talk between different Cx43 binding partners [].
Kelch repeat and BTB domain-containing protein 2, BACK domain
Type:
Domain
Description:
KBTBD2, also called BTB and kelch domain-containing protein 1 (BKLHD1), plays an essential role in the regulation of insulin-signaling pathway. It is a BTB-Kelch family substrate recognition subunit of the Cullin-3-based E3 ubiquitin ligase, which targets p85alpha, the regulatory subunit of the phosphoinositol-3-kinase (PI3K) heterodimer, causing p85alpha ubiquitination and proteasome-mediated degradation. This entry represents the BACK domain [
,
].The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs [
].
Kelch repeat and BTB domain-containing protein 3, BACK domain
Type:
Domain
Description:
The BTB superfamily includes KLHL (Kelch-like), KBTBD (Kelch repeat and BTB domain-containing), and KLHDC (Kelch domain-containing) subfamilies, which encompass structurally related molecules that differ in the types and numbers of their protein domains. The domain composition can appear to vary depending on the protein domain prediction program. For example, KLHL29, KLHL31, KLHL40, and KLHL41 were previously assigned within the KBTBD family as KBTBD9, KBTBD1, KBTBD5, and KBTBD10 respectively. KBTBD proteins have typically one BTB/POZ domain, occasionally a BACK domain, and two to four Kelch motifs [
].KBTBD3, also termed BTB and kelch domain-containing protein 3 (BKLHD3), is a BTB-Kelch family protein. Its function remains unclear. This entry represents the BACK domain [].
A kinase-anchoring protein AKAP5 and AKAP12, calmodulin (CaM)-binding motif
Type:
Domain
Description:
The AKAP CaM-binding motif (also known as the WSK motif) is short motif, named after three conserved residues found in the WXSXK motif, found in protein kinase A anchoring proteins. The A kinase-anchoring proteins AKAP-5 and AKAP-12 (Gravin) bind calmodulin (CaM), a Ca(2+)-sensing protein that is expressed in all eukaryotic cells and mediates many essential processes driven by Ca(2+), including long-term changes in synaptic connections in the brain, apoptosis, and immune responses. The AKAP CaM-binding motif contains hydrophobic amino acids in a 1-4-7-8 pattern within an helix [
].
Type VI secretion system (T6SS), amidase effector protein 4
Type:
Family
Description:
Tae4 is a new form of toxin-antitoxin system protein for a type VI secretion system, T6SS. T6SS has roles in interspecies interactions, as well as higher order host-infection, by injecting effector proteins into the periplasmic compartment of the recipient cells of closely related species. Pseudomonas aeruginosa produces at least three effector proteins to other cells and thus has three specific cognate immunity proteins to protect itself. Tae4, or type VI amidase effector 4, in Enterobacter cloacae has a cognate Tai4 or type VI amidase immunity 4 protein [
].
Protein kinase A anchor protein, nuclear localisation signal domain
Type:
Domain
Description:
This entry represents the nuclear localisation signal-containing domain found in the cyclic AMP-dependent protein kinase A (PKA) anchor protein, AKAP7. This protein anchors PKA for its role in regulating PKA-mediated gene transcription in both somatic cells and oocytes [
]. This domain carries the nuclear localisation signal (NLS) KKRKK, that indicates the cellular destiny of this anchor protein []. The domain is also found in a number of other proteins, such as activating signal cointegrator 1 complex subunit 1 and leukocyte receptor cluster member 9.
Type II secretion system protein GspM, periplasmic domain superfamily
Type:
Homologous_superfamily
Description:
GspM is part of the inner membrane component of the type II secretion system (T2SS). It consists of a short cytosolic N-terminal domain, a transmembrane domain, and a C-terminal periplasmic domain. The precise function of this protein is unknown [
]. However, though in Vibrio cholerae, the EpsM protein interacts with the EpsL protein, and also forms homodimers [].The periplasmic domain forms a sandwich consisting of two α-helices and a four-stranded antiparallel β-sheet [
]. The overall fold is a circular permutation of the ferredoxin fold. In the dimer, a deep cleft with a polar rim and a hydrophobic bottom made by conserved residues is located between the monomers. This cleft contains an extra electron density suggesting that this region might serve as a binding site of an unknown ligand or part of a protein partner.
Maltose transport system permease protein MalF, P2 domain superfamily
Type:
Homologous_superfamily
Description:
The maltose transport system is composed of a periplasmic maltose-binding protein (MBP), two integral membrane proteins, MalF and MalG, and two copies of the cytoplasmic ATP-binding cassette MalK [
]. The structures of the two transmembrane (TM) subunits, MalF and MalG, are composed of eight and six TM helices, respectively. The TM helices of MalF and MalG assemble into two crescent shaped structures with their concave surfaces facing each other and enclosing the maltose. MalF consists of four periplasmic domains. This entry represents the second periplasmic loop of MalF (P2), which binds to MalE and is involved in activation of the MalFGK2-E complex by inducing structural changes in maltose-bound MalE []. P2 is also responsible for substrate recognition [,
,
].
BTB/POZ domain-containing adapter for CUL3-mediated RhoA degradation protein 1/2/3
Type:
Family
Description:
This entry represents a group of BTB/POZ domain-containing proteins, such as BACURD1-3 from humans. They act as the substrate-specific adapters of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex, which mediates the ubiquitination of RhoA, leading to its degradation by the proteasome [
]. This entry also includes EAP3 from Arabidopsis. The BTB/POZ domain of EAP3 displays poor conservation of the residues required for CUL3 binding and is not likely to function as an E3 ligase adaptor [].
RecQ mediated genome instability protein 1-like, N-terminal helical domain
Type:
Domain
Description:
This entry represents the N-terminal helical domain of RMI 1 (RecQ-mediated genome instability protein 1) and similar proteins [
]. This domain is found at the N-terminal of an oligo-nucleotide-binding domain or OB-fold, and forms a stable complex with Bloom syndrome protein BLM and DNA topoisomerase 3-alpha [,
].
High-affinity branched-chain amino acid transport system permease protein LivM-like
Type:
Family
Description:
This entry includes transmembrane subunit (TM) of Escherichia coli LivM, Pseudomonas aeruginosa BraE, and related proteins. LivM is one of two TMs of the E. coli LIV-1/LS transporter, a Periplasmic Binding Protein (PBP)-dependent ATP-Binding Cassette (ABC) transporter involved in the uptake of branched-chain amino acids (AAs). These types of transporters generally bind type 1 PBPs. PBP-dependent ABC transporters consist of a PBP, two TMs, and two cytoplasmic ABCs, and are mainly involved in importing solutes from the environment. The solute is captured by the PBP, which delivers it to a gated translocation pathway formed by the two TMs. The two ABCs bind and hydrolyze ATP and drive the transport reaction [
,
]. E. coli LivM forms a heterodimer with another TM, LivH, to generate the transmembrane pore. LivH is not included in this subgroup. The LIV-1/LS transporter is comprised of two TMs (LivM and LivH), two ABCs (LivG and LivF), and one of two alternative PBPs, LivJ (LIV-BP) or LivK (LS-BP). In addition to transporting branched-chain AAs including leucine, isoleucine and valine, the E. coli LIV-1/LS transporter is involved in the uptake of the aromatic AA, phenylalanine [
,
,
].
RNA-binding protein Nova-1/2, type I K Homology domain 3
Type:
Domain
Description:
This entry represents the third type I K homology (KH) RNA-binding domain found in Nova-1 and Nova-2.This group of proteins includes related neuronal RNA-binding proteins, such as Nova-1 and Nova-2. Nova-1 may regulate RNA splicing or metabolism in a specific subset of developing neurons. It interacts with RNA containing repeats of the YCAY sequence. It is a brain-enriched splicing factor regulating neuronal alternative splicing. Nova-1 is involved in neurological disorders and carcinogenesis. Nova-2 is a neuronal RNA-binding protein expressed in a broader central nervous system (CNS) distribution than Nova-1. It functions in neuronal RNA metabolism. NOVA family proteins contain three K-homology (KH) RNA-binding domains [
,
,
,
,
,
,
,
,
,
]. This entry also includes the homologue of Nova1 in Drosophila melanogaster, also know as RNA-binding protein Pasilla, which plays a role in long-term memory formation by processing the unspliced Orb2-isoform A (Orb2A) mRNA and thereby controlling Orb2A protein abundance [
,
].
RNA-binding protein Nova-1/2, type I K Homology domain 1
Type:
Domain
Description:
This entry represents the first type I K homology (KH) RNA-binding domain found in Nova-1 and Nova-2.This group of proteins includes related neuronal RNA-binding proteins, such as Nova-1 and Nova-2. Nova-1 may regulate RNA splicing or metabolism in a specific subset of developing neurons. It interacts with RNA containing repeats of the YCAY sequence. It is a brain-enriched splicing factor regulating neuronal alternative splicing. Nova-1 is involved in neurological disorders and carcinogenesis. Nova-2 is a neuronal RNA-binding protein expressed in a broader central nervous system (CNS) distribution than Nova-1. It functions in neuronal RNA metabolism. NOVA family proteins contain three K-homology (KH) RNA-binding domains [
,
,
,
,
,
,
,
,
,
]. This entry also includes the homologue of Nova1 in Drosophila melanogaster, also know as RNA-binding protein Pasilla, which plays a role in long-term memory formation by processing the unspliced Orb2-isoform A (Orb2A) mRNA and thereby controlling Orb2A protein abundance [
,
].
RNA-binding protein Nova-1/2, type I K Homology domain 2
Type:
Domain
Description:
This entry represents the second type I K homology (KH) RNA-binding domain found in Nova-1 and Nova-2.This group of proteins includes related neuronal RNA-binding proteins, such as Nova-1 and Nova-2. Nova-1 may regulate RNA splicing or metabolism in a specific subset of developing neurons. It interacts with RNA containing repeats of the YCAY sequence. It is a brain-enriched splicing factor regulating neuronal alternative splicing. Nova-1 is involved in neurological disorders and carcinogenesis. Nova-2 is a neuronal RNA-binding protein expressed in a broader central nervous system (CNS) distribution than Nova-1. It functions in neuronal RNA metabolism. NOVA family proteins contain three K-homology (KH) RNA-binding domains [
,
,
,
,
,
,
,
,
,
]. This entry also includes the homologue of Nova1 in Drosophila melanogaster, also know as RNA-binding protein Pasilla, which plays a role in long-term memory formation by processing the unspliced Orb2-isoform A (Orb2A) mRNA and thereby controlling Orb2A protein abundance [
,
].
Type IV secretion system coupling protein TraD, DNA-binding domain
Type:
Domain
Description:
The plasmid conjugative coupling protein TraD (also known as TrwB) is a basic integral inner-membrane nucleoside-triphosphate-binding protein. It is the structural prototype for the type IV secretion system coupling proteins, a family of proteins essential for macromolecular transport between cells [
]. This protein forms hexamers from six structurally very similar protomers []. This hexamer contains a central channel running from the cytosolic pole (formed by the all-α domains) to the membrane pole ending at the transmembrane pore shaped by 12 transmembrane helices, rendering an overall mushroom-like structure. The TrwB all-α domain appears to be the DNA-binding domain of the structure.
Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment
Type:
Domain
Description:
ATS is the intracellular and relatively conserved acidic terminal segment of the Plasmodium falciparum erythrocyte membrane protein-1 (PfEMP1) [
]. This domain appears to be present in all variants of the highly polymorphic PfEMP1 proteins.
LEAF RUST 10 DISEASE-RESISTANCE LOCUS RECEPTOR-LIKE PROTEIN KINASE-like 1.1/1.2/1.3/1.4/1.5
Type:
Family
Description:
This entry represents a group of plant putative receptor-like kinases, including LRK10L-1.1/1.2/1.3/1.4 and wall-associated receptor kinase-like 14/15/21 from Arabidopsis [
]. LRK10L-1.2 is involved in ABA-mediated signaling and drought resistance []. This entry also includes CRCK1 which has high homology in the kinase domain to serine/threonine receptor-like kinases. However, it does not have a transmembrane domain nor an extracellular domain. It binds calmodulin in a calcium-dependent manner, which stimulates its kinase activity. Stress factors like cold, salt or abscisic acid and hydrogen peroxide increase CRCK1 expression which suggests that it functions as a calcium/calmodulin-regulated receptor-like cytoplasmic kinase involved in stress response [].
AT-rich interactive domain-containing protein 1A, ARID/BRIGHT DNA binding domain
Type:
Domain
Description:
AT-rich interactive domain-containing protein 1A (ARID1A or BAF250a) is part of the SWI/SNF-like ATP-dependent chromatin remodelling complex that regulates gene expression through regulating nucleosome remodelling [
,
]. In humans there are two BAF250 isoforms, BAF250a/ARID1A and BAF250b/ARID1B []. Both BAF250a and BAF250b bind DNA non-specifically []. They are thought to be E3 ubiquitin ligases that target histone H2B []. BAF250a plays key roles in maintaining embryonic stem cell pluripotency and in cardiac development and function [,
]. The BAF250a gene is a tumour suppressor gene that is frequently mutated in ovarian clear cell carcinoma [].This entry represents the ARID/BRIGHT DNA binding domain of ARI1A. It binds DNA in a non-sequence-specific manner similar to ARID1B [
].
AT-rich interactive domain-containing protein 5B, ARID/BRIGHT DNA binding domain
Type:
Domain
Description:
ARID5B, also known as modulator recognition factor-2 (Mrf-2), is a member of the AT-rich interaction domain (ARID) family of transcription factors [
]. Human ARID5B forms complex with PHF2, a jmjC demethylase; this complex serves as a signal-sensing modulator of histone methylation and gene transcription []. It facilitates chondrogenesis by recruiting the histone demethylase PHF2 to Sox9-regulated genes []. Mouse Mrf-2 is required for adipogenesis and to maintain normal functions in mature adipocytes []. The genetic variations in the ARID5B gene have been linked to susceptibility to type 2 diabetes [
], acute lymphoblastic leukemia [] and coronary atherosclerosis []. This entry represents the AT-rich ARID/BRIGHT DNA binding domain of ARID5B.
RecQ-mediated genome instability protein 1, N-terminal helical domain superfamily
Type:
Homologous_superfamily
Description:
This entry represents the N-terminal helical domain of RMI 1 (RecQ-mediated genome instability protein) proteins from metazoa [
]. This domain is found at the N-terminal of an oligo-nucleotide-binding domain or OB-fold, and forms a stable complex with Bloom syndrome protein BLM and DNA topoisomerase 3-alpha [,
].
TATA box binding protein associated factor (TAF), histone-like fold domain
Type:
Domain
Description:
The TATA box binding protein associated factor (TAF) is part of the transcription initiation factor TFIID multimeric protein complex. TFIID plays a central role in mediating promoter responses to various activators and repressors. It binds tightly to TAFII-250 and directly interacts with TAFII-40. TFIID is composed of TATA binding protein (TBP) and a number of TBP-associated factors (TAFS). TAF proteins adopt a histone-like fold [
,
].The DNA-binding general transcription factor complex TFIID is central to the initiation of DNA-dependent RNA polymerase II transcription. TFIID is the only general transcription initiation factor that bind to the TATA box. The binding of TFIID to the TATA-box is the first step in the formation of a complex able to initiate transcription [
]. TFIID consists of the TATA binding protein (TBP) and 14 TBP-associated factors (TAFs). One copy of each TAF1, TAF2, TAF3, TAF7, TAF8, TAF11, TAF13, two copies of each TAF4, TAF5, TAF6, TAF9, TAF10, TAF12, and three copies of TAF14 [].
Vacuolar sorting protein 39/Transforming growth factor beta receptor-associated domain 2
Type:
Domain
Description:
This entry represents a domain found in the vacuolar sorting protein Vps39 and transforming growth factor beta receptor-associated protein Trap1. Vps39, a component of the C-Vps complex, is thought to be required for the fusion of endosomes and other types of transport intermediates with the vacuole [
,
]. In Saccharomyces cerevisiae (Baker's yeast), Vps39 has been shown to stimulate nucleotide exchange []. Trap1 plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling [,
]. The precise function of this domain has not been characterised In Vps39 this domain is involved in localisation and in mediating the interactions with Vps11 [].
Vacuolar sorting protein 39/Transforming growth factor beta receptor-associated domain 1
Type:
Domain
Description:
This entry represents a domain found in the vacuolar sorting protein Vps39 and transforming growth factor beta receptor-associated protein Trap1. Vps39, a component of the C-Vps complex, is thought to be required for the fusion of endosomes and other types of transport intermediates with the vacuole [
,
]. In Saccharomyces cerevisiae (Baker's yeast), Vps39 has been shown to stimulate nucleotide exchange []. Trap1 plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling [,
]. The precise function of this domain has not been characterised.
Zinc finger ZZ-type and EF-hand domain-containing protein 1, APC10/DOC1-like domain
Type:
Domain
Description:
This group of proteins is found in animals and includes Zinc finger ZZ-type and EF-hand domain-containing protein 1 (ZZEF1). ZZEF1 is a histone H3 reader which may act as a transcriptional coactivator for KLF6 and KLF9 transcription factors [
].This entry represents the APC10/DOC1-like domain of ZZEF1. It is homologous to the APC10 subunit/DOC1 domains present in E3 ubiquitin ligases (
), which mediate substrate ubiquitination (or ubiquitylation), and are components of the ubiquitin-26S proteasome pathway for selective proteolytic degradation.
ABC transporter, CydDC cysteine exporter (CydDC-E) family, permease/ATP-binding protein CydD
Type:
Family
Description:
The gene pair cydCD encodes an ABC-family transporter in which each gene contains an N-terminal membrane-spanning domain and a C-terminal ATP-binding domain [
]. In Escherichia coli these genes were discovered as mutants which caused the terminal haem-copper oxidase complex cytochrome bd to fail to assemble. Recent work has shown that the transporter is involved in the export of redox-active thiol compounds such as cysteine and glutathione [,
]. The linkage to assembly of the cytochrome bd complex is further supported by the conserved operon structure found outside the gammaproteobacteria (cydABCD) containing both the transporter and oxidase genes components.
ABC transporter, CydDC cysteine exporter (CydDC-E) family, permease/ATP-binding protein CydC
Type:
Family
Description:
ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily, which uses the hydrolysis of ATP to energise diverse biological systems. ABC transporters minimally consist of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These can be found on the same protein or on two different ones. Most ABC transporters function as a dimer and therefore are constituted of four domains, two ABC modules and two TMDs.ABC transporters are involved in the export or import of a wide variety of substrates ranging from small ions to macromolecules. The major function of ABC import systems is to provide essential nutrients to bacteria. They are found only in prokaryotes and their four constitutive domains are usually encoded by independent polypeptides (two ABC proteins and two TMD proteins). Prokaryotic importers require additional extracytoplasmic binding proteins (one or more per systems) for function. In contrast, export systems are involved in the extrusion of noxious substances, the export of extracellular toxins and the targeting of membrane components. They are found in all living organisms and in general the TMD is fused to the ABC module in a variety of combinations. Some eukaryotic exporters encode the four domains on the same polypeptide chain [
].The ABC module (approximately two hundred amino acid residues) is known to bind and hydrolyse ATP, thereby coupling transport to ATP hydrolysis in a large number of biological processes. The cassette is duplicated in several subfamilies. Its primary sequence is highly conserved, displaying a typical phosphate-binding loop: Walker A, and a magnesium binding site: Walker B. Besides these two regions, three other conserved motifs are present in the ABC cassette: the switch region which contains a histidine loop, postulated to polarise the attaching water molecule for hydrolysis, the signature conserved motif (LSGGQ) specific to the ABC transporter, and the Q-motif (between Walker A and the signature), which interacts with the gamma phosphate through a water bond. The Walker A, Walker B, Q-loop and switch region form the nucleotide binding site [,
,
].The 3D structure of a monomeric ABC module adopts a stubby L-shape with two distinct arms. ArmI (mainly β-strand) contains Walker A and Walker B. The important residues for ATP hydrolysis and/or binding are located in the P-loop. The ATP-binding pocket is located at the extremity of armI. The perpendicular armII contains mostly the alpha helical subdomain with the signature motif. It only seems to be required for structural integrity of the ABC module. ArmII is in direct contact with the TMD. The hinge between armI and armII contains both the histidine loop and the Q-loop, making contact with the gamma phosphate of the ATP molecule. ATP hydrolysis leads to a conformational change that could facilitate ADP release. In the dimer the two ABC cassettes contact each other through hydrophobic interactions at the antiparallel β-sheet of armI by a two-fold axis [
,
,
,
,
,
].The ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions [
]. Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette [
,
]. More than 50 subfamilies have been described based on a phylogenetic and functional classification [,
,
].This entry represents CydC, a member of a heterodimeric ATP-binding cassette-type transporter (ABC transporter). It is involved in the export of glutathione from the cytoplasm to the periplasm and is required for the assembly of both cytochrome c and cytochrome bd [
,
,
]. The homologue of CydC in B. subtilis is referred to as CydD [].
Ankyrin repeat and SAM domain-containing protein 1, SAM repeat 2
Type:
Domain
Description:
This SAM (sterile alpha motif) domain repeat 2 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability [
]. ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions []. Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain []. SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor []. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus [].
Ankyrin repeat and SAM domain-containing protein 1, SAM repeat 1
Type:
Domain
Description:
This SAM (sterile alpha motif) domain repeat 1 of ANKS1 (also known as AIDA-1) is a protein-protein interaction domain.Proteins contain this domain include ANKS1A (also known as Odin) and ANKS1B (also known as AIDA-1 or EB-1). ANKS1A modulates EGF receptor recycling and stability [
]. ANKS1B may participate in the regulation of nucleoplasmic coilin protein interactions []. Structurally, ANKS1 consist of N-terminal ankyrin motifs followed by two tandem sterile alpha motif (SAM) domains and a carboxyl phosphotyrosine binding (PTB) domain []. SAM domains of ANKS1 can directly bind ubiquitin and participate in regulating the degradation of ubiquitinated EphA receptors, particularly EPH-A8 receptor []. SAM1 domain has a potential phosphorylation site for CMGC group of serine/threonine kinases. The second SAM domain may decouple from the first SAM domain to facilitate translocation of AIDA-1 to the nucleus [].
Protein of unknown function DUF1786, putative pyruvate format-lyase activating enzyme
Type:
Family
Description:
This family is annotated as pyruvate formate-lyase activating enzyme (
) in UniProt. Pyruvate formate-lyase (PFL) catalyses the non-oxidative dissimilation of pyruvate to formate and acetyl-CoA using a radical-chemical mechanism [
].
Putative variant cofactor biosynthesis B12-binding domain/radical SAM domain protein 1
Type:
Family
Description:
Members of this protein family are one of two tandem B12-binding domain/radical SAM domain proteins that occur in a genome context with a pair of homologues to ThiC (phosphomethylpyrimidine synthase,
), an enzyme that performs a complex rearrangement involved in thiamin biosynthesis, and a putative CobT (nicotinate-nucleotide--dimethylbenzimidazole phosphoribosyltransferase), an enzyme of cobalamin biosynthesis.
Spike (S) protein S1 subunit, N-terminal domain, murine hepatitis virus-like
Type:
Domain
Description:
The CoV Spike (S) protein is an envelope glycoprotein that plays the most important role in viral attachment, fusion, and entry into host cells, and serves as a major target for the development of neutralizing antibodies, inhibitors of viral entry, and vaccines. It is synthesised as a precursor protein that is cleaved into an N-terminal S1 subunit (~700 amino acids) and a C-terminal S2 subunit (~600 amino acids) that mediates attachment and membrane fusion, respectively. Three S1/S2 heterodimers assemble to form a trimer spike protruding from the viral envelope. The S1 subunit contains a receptor-binding domain (RBD), while the S2 subunit contains a hydrophobic fusion peptide and two heptad repeat regions. S1 contains two structurally independent domains, the N-terminal domain (NTD) and the C-terminal domain (C-domain). Depending on the virus, either the NTD or the C-domain can serve as the receptor-binding domain (RBD). Most CoVs, including SARS-CoV-2, SARS-CoV, and MERS-CoV use the C-domain to bind their receptors. However, CoV such as mouse hepatitis virus (MHV) uses the NTD to bind its receptor, mouse carcinoembryonic antigen related cell adhesion molecule 1a (mCEACAM1a). The S1 NTD contributes to the Spike trimer interface [
,
,
,
].This entry represents the N-terminal domain (NTD) of the S1 subunit of the Spike (S) proteins from betacoronaviruses in the embecovirus subgenera (A lineage), including murine hepatitis virus (MHV), human coronavirus (HCoV) HKU1 and OC43, and bovine CoV (BCoV). MHV is the most common viral pathogen in contemporary laboratory mouse colonies manifesting as a primary infection in the upper respiratory tract, while HCoV-HKU1 causes mild yet prevalent respiratory disease in humans [
].
Non-structural protein 3c (NS3c), Middle East respiratory syndrome (MERS)-related CoV
Type:
Family
Description:
This entry represents the accessory protein 4b, ORF4b (also called NS3c protein) of Middle East respiratory syndrome (MERS)-related CoV, as well as some bat coronaviruses.ORF4b/NS3c plays a role in the inhibition of host innate immunity by inhibiting the interaction between host IkappaB kinase epsilon (IKBKE or IKKE) and mitochondrial antiviral-signalling protein (MAVS). In turn, this inhibition prevents the production of host interferon beta. Additionally, it may also interfere with host antiviral response within the nucleus. ORF4b/NS3c proteins in this subgroup are similar to the MERS-CoV ORF4b (also known as MERS-CoV 4b) which has been shown to interfere with the NF-kappaB-dependent innate immune response during infection, as well as antagonizing the early antiviral alpha/beta interferon (IFN-alpha/beta) response, which may significantly contribute to MERS-CoV pathogenesis [
,
,
,
].
