MyoD family inhibitor/MyoD family inhibitor domain-containing protein
Type:
Family
Description:
This family consists of MyoD family inhibitor (I-mfa, MDFI) and MyoD family inhibitor domain-containing protein. I-mfa acts as a transcriptional activator or repressor. It retains nuclear Zic family proteins (ZIC1, ZIC2 and ZIC3) in the cytoplasm and consequently inhibits their transcriptional activation ability [
]. I-mfa domain-containing protein interacts with HAND1 (bHLH transcription factor), leading to sequester HAND1 into the nucleolus and prevent its activity [
]. In humans modulates the expression from both cellular and viral promoters. It down-regulates Tat-dependent transcription of the human immunodeficiency virus type 1 (HIV-1) LTR by interacting with HIV-1 Tat and Rev and impairing their nuclear import, probably by rendering the NLS domains inaccessible to importin-beta. It also stimulates activation of human T-cell leukemia virus type I (HTLV-I) LTR [,
,
]. Both I-mfa and I-mfa domain-containing protein interact with the axin complex and affect axin regulation of both the Wnt and the JNK activation pathways [
].
Resistance to inhibitors of cholinesterase protein 3
Type:
Family
Description:
Human Ric3 promotes functional expression of homomeric alpha-7 and alpha-8 nicotinic acetylcholine receptors at the cell surface. It may also promote functional expression of homomeric serotoninergic 5-HT3 receptors, and of heteromeric acetylcholine receptors alpha-3/beta-2, alpha-3/beta-4, alpha-4/beta-2 and alpha-4/beta-4 [
,
,
,
,
,
]. C. elegans Ric3 is required for maturation and cell surface expression of acetylcholine receptors [
,
,
].
NADH dehydrogenase [ubiquinone] iron-sulfur protein 6, mitochondrial
Type:
Family
Description:
NDUFS6 is an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), that is believed not to be involved in catalysis [
]. It harbours a Zn-binding site and is essential for biogenesis of mitochondrial complex I [].
This is the alpha-crystallin domain (ACD) found in Escherichia coli inclusion body-associated proteins IbpA and IbpB, and similar proteins. This domain is also found in class A small heat shock proteins from Bradyrhizobium, which consists of proteins that show similarity to E. coli IbpA and IbpB [
].IbpA and IbpB are 16kDa small heat shock proteins (sHsps). sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits. They all contain a conserved alpha-crystallin domain flanked by variable N- and C-terminal tails [
]. IbpA and IbpB are produced during high-level production of various heterologous proteins, specifically human prorenin, renin and bovine insulin-like growth factor 2 (bIGF-2), and are strongly associated with inclusion bodies containing these heterologous proteins []. IbpA and IbpB work as an integrated system to stabilize thermally aggregated proteins in a disaggregation competent state []. The chaperone activity of IbpB is also significantly elevated as the temperature increases from normal to heat shock. The high temperature results in the disassociation of 2-3-MDa IbpB oligomers into smaller approximately 600kDa structures. This elevated activity seen under heat shock conditions is retained for an extended period of time after the temperature is returned to normal [
]. IbpA also forms multimers [].
Heat shock protein beta-8, alpha-crystallin domain (ACD)
Type:
Domain
Description:
This entry represents the alpha-crystallin domain (ACD) found in mammalian 21.6 kDa small heat shock protein (sHsp) HspB8, also known as Hsp22 in humans [
]. sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits []. A chaperone complex formed of HspB8 and Bag3 stimulates degradation of protein complexes by macroautophagy [,
]. HspB8 also forms complexes with Hsp27 (HspB1), MKBP (HspB2), HspB3, alphaB-crystallin (HspB5), Hsp20 (HspB6), and cvHsp (HspB7). These latter interactions may depend on phosphorylation of the respective partner sHsp. HspB8 may participate in the regulation of cell proliferation, cardiac hypertrophy, apoptosis, and carcinogenesis [,
].Point mutations in HspB8 have been correlated with the development of several congenital neurological diseases, including Charcot Marie tooth disease and distal motor neuropathy type II [
,
].
Golgi-associated plant pathogenesis-related protein 1, SCP domain
Type:
Domain
Description:
This SCP-like extracellular protein domain is found in golgi-associated plant pathogenesis-related protein 1 (GAPR-1).The human GAPR-1 protein has been reported to dimerize, and such a dimer may form an active site containing a catalytic triad. GAPR-1 and GLIPR-2 appear to be synonyms [
,
].The SCP domain is also known as CAP domain [
]. The wider family of SCP containing proteins includes plant pathogenesis-related protein 1 (PR-1), CRISPs, mammalian cysteine-rich secretory proteins, which combine SCP with a C-terminal cysteine rich domain, and allergen 5 from vespid venom. It has been proposed that SCP domains may function as endopeptidases.
AT-rich interactive domain-containing protein 1B, ARID domain
Type:
Domain
Description:
AT-rich interactive domain-containing protein 1B (ARID1B or BAF250b) 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 []. BAF250b is also a component of the BAF [], SWI/SNF-like EBAFb [], npBAF and nBAF complexes [], which remodel chromatin. ARID1B exhibits tumour-suppressor activities in pancreatic cancer cell lines [, [cite:]]. Mutations in the ARID1B gene cause Coffin-Siris syndrome, exhibiting developmental defects, and haplo-insufficiency of ARID1B, a frequent cause of intellectual disability [,
]. Moreover, mutations in the ARID1B gene have been found in many cancers []. This entry represents the ARID/BRIGHT DNA binding domain of ARI1B. It binds DNA in a non-sequence-specific manner similar to ARID1A [
].
PHD finger protein 10 (PHF10 or BAF45A) is a component of the npBAF complex, which remodels chromatin, a mechanism by which selected genes are transcriptionally activated or repressed [
].The npBAF and nBAF complexes are found in neural progenitor cells. The npBAF complex is composed of at least ARID1A/BAF250A or ARID1B/BAF250B, SMARCD1/BAF60A, SMARCD3/BAF60C, SMARCA2/BRM/BAF190B, SMARCA4/BRG1/BAF190A, SMARCB1/BAF47, SMARCC1/BAF155, SMARCE1/BAF57, SMARCC2/BAF170, PHF10/BAF45A, ACTL6A/BAF53A and actin. During development, as neural stem cells differentiate post-mitotic chromatin remodeling mechanism occurs, accompanied by a change in the composition of the npBAF complex to form the nBAF complex. The subunits ACTL6A/BAF53A and PHF10/BAF45A are exchanged for ACTL6B/BAF53B and DPF1/BAF45B or DPF3/BAF45C. The nBAF complex along with CREST plays a role regulating the activity of genes essential for dendrite growth [
].This entry represents the first PHD finger of PHF10.
4-HPA 3-monooxygenase large component/Pyoverdin chromophore biosynthetic protein
Type:
Family
Description:
4-hydroxyphenylacetate (4HPA) 3-monooxygenase consists of two components, a large component, HpaB, which is an oxygenase, and a small component, HpaC, which is a reductase. 4-HPA 3-monooxygenase is NADH-dependent and uses FAD as the redox chromophore. HpaB utilises FADH2 supplied by HpaC to catalyse the hydroxylation of 4-hydroxyphenylacetic acid, leading to the production of 3,4-dihydroxyphenylacetic acid (DHPA) [
].This entry represents the 4-HPA 3-monooxygenase large component, HpaB. It also represents the related enzyme pyoverdin chromophore biosynthetic protein (pvcC), which may play a role in one of the proposed hydroxylation steps of pyoverdine chromophore biosynthesis [
].
Bacterial general secretion pathway protein G-type pilin
Type:
Family
Description:
The general (type II) secretion pathway (GSP) within Gram-negative bacteria is a signal sequence-dependent process responsible for protein export [
,
,
], including virulence factors. The process has two stages, exoproteins are first translocated across the inner membrane by the general signal-dependent export pathway (GEP), and then across the outer membrane by a species-specific accessory mechanism. One of the proteins involved in the GSP is termed general secretion pathway protein G (GSPG). This protein shares several sequence similarities with bacterial fimbrial protein, or pilin, the major structural protein of pili [,
]. Pili are polar flexible filamentous adhesions ~2500 nm in length, and diameter ~5.4 nm. Fimbrial and GSPG proteins share the following characteristics; a methylated, hydrophobic N-terminal residue; a hydrophobic leader peptide of 5-10 residues, terminating with glycine; glutamate as the fifth residue of the mature sequence; and a highly hydrophobic N-terminal. This system is homologous to the type IV pilus biogenesis and includes different proteins, termed psudopilins, which are structurally homologous to the type IV pilins [,
].
Protein of unknown function DUF267, Caenorhabditis species
Type:
Family
Description:
This family of proteins, from Caenorhabditis species, have not been characterised though a number are annotated as 'serpentine receptor, class r' proteins.
Intermembrane lipid transfer protein VPS13D, UBA domain
Type:
Domain
Description:
This entry represents the UBA domain of the intermembrane lipid transfer protein VP13D (also known as vacuolar protein sorting-associated protein 13D), which is a ubiquitin-binding protein that contains two putative domains, ubiquitin-associated (UBA) domain and lectin domain of ricin B chain profile (ricin-B-lectin) [
]. The UBA domain of Vps13D has been shown to bind K63 ubiquitin chains. Vps13D plays important roles in mitochondrial health and development. It is also necessary for autophagy, mitochondrial size, and mitochondrial clearance in Drosophila [].
Streptococcal surface-anchored protein repeat, S. criceti family
Type:
Repeat
Description:
This entry represents a repeat sequence that occurs primarily in LPXTG-anchored Streptococcus surface proteins, although it does occur elsewhere. It can comprise a major fraction of the length of repeat proteins that exceed 2000 amino acids in length. This repeat is flanked by collagen-like CXX motifs.
Tumor necrosis factor alpha-induced protein 8-like superfamily
Type:
Homologous_superfamily
Description:
Four tumor necrosis factor alpha-induced protein 8-like proteins have been identified: TNFAIP8 (also known as TIPE), TIPE1, TIPE2 and TIPE3. Overexpressed TIPE in cells can reduce cell death in vitro and increase tumor growth in vivo [
]. By contrast, TIPE2 has been demonstrated to be an inhibitor of Ras and to have a pro-apoptotic ability. TIPE1 could upregulate the pro-apoptotic members of the B-cell leukemia/lymphoma (Bcl)-2 family of proteins [].
Proteolytic enzymes that exploit serine in their catalytic activity are ubiquitous, being found in viruses, bacteria and eukaryotes [
]. They include a wide range of peptidase activity, including exopeptidase, endopeptidase, oligopeptidase and omega-peptidase activity. Many families of serine protease have been identified, these being grouped into clans on the basis of structural similarity and other functional evidence []. Structures are known for members of the clans and the structures indicate that some appear to be totally unrelated, suggesting different evolutionary origins for the serine peptidases [].Not withstanding their different evolutionary origins, there are similarities in the reaction mechanisms of several peptidases. Chymotrypsin, subtilisin and carboxypeptidase C have a catalytic triad of serine, aspartate and histidine in common: serine acts as a nucleophile, aspartate as an electrophile, and histidine as a base [
]. The geometric orientations of the catalytic residues are similar between families, despite different protein folds []. The linear arrangements of the catalytic residues commonly reflect clan relationships. For example the catalytic triad in the chymotrypsin clan (PA) is ordered HDS, but is ordered DHS in the subtilisin clan (SB) and SDH in the carboxypeptidase clan (SC) [,
].SpoIVB, the stage IV sporulation protein B of endospore-forming bacteria such as Bacillus subtilis, is a serine proteinase expressed in the spore (rather than mother cell) compartment, that participates in a proteolytic activation cascade for Sigma-K. It appears to be universal among endospore-forming bacteria and occurs nowhere else. The members of this entry belong to MEROPS peptidase family S55 (SpoIVB peptidase, clan PA).
Accessory Sec system protein translocase subunit SecY2
Type:
Family
Description:
Members of this family are restricted to the Firmicutes lineage (low-GC Gram-positive bacteria) and appear to be paralogous to, and much more divergent than, the preprotein translocase SecY. Members include the SecY2 protein of the accessory Sec system in Streptococcus gordonii, involved in export of the highly glycosylated platelet-binding protein GspB [
].
Protein disulfide-isomerase A5, N-terminal TRX-like b domain
Type:
Domain
Description:
This entry represents the N-terminal TRX-like b domain found in protein disulfide-isomerase A5 (PDIA5, also known as PDIR). PDIR is composed of three redox active TRX (a) domains and an N-terminal redox inactive TRX-like (b) domain. Similar to PDI, it is involved in oxidative protein folding in the endoplasmic reticulum (ER) through its isomerase and chaperone activities. These activities are lower compared to PDI, probably due to PDIR acting only on a subset of proteins. PDIR is preferentially expressed in cells actively secreting proteins and its expression is induced by stress [
]. Similar to PDI, the isomerase and chaperone activities of PDIR are independent; CXXC mutants lacking isomerase activity retain chaperone activity. The TRX-like b domain of PDIR is critical for its chaperone activity [].
Vesicular, overexpressed in cancer, prosurvival protein 1
Type:
Family
Description:
Ectopic expression of vesicular, over-expressed in cancer, pro-survival protein 1, VOPP1 (formerly known as EGFR-co-amplified and over- expressed protein (ECop)) increases NF-kappaB transcriptional activity [
]. This is achieved by promoting nuclear translocation and DNA binding of NF-kappaB. Ecop-induced NF-kappaB activation confers cellular resistance to apoptotic challenge []. It is believed that ECop is a key regulator of NF-kappaB signalling, and that high-level, amplification-mediated ECop expression, such as occurs in tumours with amplified EGFR, may contribute to resistance to apoptosis [].
Uncharacterised conserved protein UCP020479, signal transduction CheW-like
Type:
Family
Description:
Members of this group of proteins from Proteobacteria contain a CheW-like chemotaxis signal transduction domain and an uncharacterised N-terminal domain. They are predicted to be signal transduction proteins, possibly involved in chemotaxis. The N-terminal domain is distantly related to periplasmic/solute binding domains.There are no experimental data for members of this group.
NADH dehydrogenase ubiquinone Fe-S protein 4-like superfamily
Type:
Homologous_superfamily
Description:
This entry includes NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUS4), an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), initially identified in Neurospora crassa as a 21kDa protein [,
]. It is believed that members of this family are not involved in catalysis. This entry also includes uncharacterised bacterial sequences.
Two-component sensor protein CpxA, periplasmic domain superfamily
Type:
Homologous_superfamily
Description:
The Cpx system is one of extracytoplasmic stress response systems (ESR) found in Gram-negative bacteria. ESRs are operated by a two-component signaling system which consists of a sensory histidine kinase (HK) and a response regulator (RR) as basal elements. In the Cpx system, CpxA is the inner membrane-spanning, sensory HK [
].This entry represents the periplasmic domain (also known as the VpCpxA-peri domain) of Vibrio parahaemolyticus CpxA. The VpCpxA-peri domain possesses a PAS fold that play a role in sensing envelope stress signals [
]. It recognises KCl and RbCl (Matilla et. al., FEMS Microbiology Reviews, fuab043, 45, 2021, 1. https://doi.org/10.1093/femsre/fuab043).
Lymphocyte antigen 6 complex locus protein G6d/G6f
Type:
Family
Description:
This entry includes lymphocyte antigen 6 complex locus protein G6d and G6f, which are encoded in the MHC (major histocompatibility complex). Human and mouse G6d was found to be GPI-anchored cell surface proteins, highly expressed at the leading edges of cells, on filopodia, which are normally involved in cell adhesion and migration. The human G6f protein may play a role in the downstream signal transduction pathways involving GRB2 and GRB7, including the Ras-MAP kinase pathway [
].
Non-structural protein NSP3, SUD-M domain superfamily, betacoronavirus
Type:
Homologous_superfamily
Description:
The multi-domain non-structural protein NSP3 is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. While some of the domains differ between CoV genera, eight domains of NSP3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2pro), the NSP3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. There are also two transmembrane regions, TM1 and TM2, which exist in all CoVs [
].SUD consists of three globular domains separated by short linker peptide segments: SUD-N, SUD-M, and SUD-C [
]. Among these, SUD-N and SUD-M are macrodomains. The SUD-N domain is a related macrodomain which also binds G-quadruplexes []. While SUD-N is specific to the NSP3 of SARS and betacoronaviruses of the sarbecovirus subgenera (B lineage), SUD-M is present in most NSP3 proteins except the NSP3 from betacoronaviruses of the embecovirus subgenera (A lineage). SUD-M, despite its name, is not specific to SARS. SUD-C adopts a frataxin-like fold, has structural similarity to DNA-binding domains of DNA-modifying enzymes, binds single-stranded RNA, and regulates the RNA binding behavior of the SUD-M macrodomain. SARS-CoV Nsp3 contains a third macrodomain (the X-domain). The X-domain may function as a module binding poly(ADP-ribose); however, SUD-N and SUD-M do not bind ADP-ribose, as the triple glycine sequence involved in its binding is not conserved in these [].
Nitrous oxide reductase family maturation protein NosD
Type:
Family
Description:
Members of this family include NosD, a repetitive periplasmic protein required for the maturation of the copper-containing enzyme nitrous-oxide reductase. NosD appears to be part of a complex with NosF (an ABC transporter family ATP-binding protein) and NosY (a six-helix transmembrane protein in the ABC-2 permease family). However, NosDFY-like complexes appear to occur also in species whose copper requiring enzymes are something other than nitrous-oxide reductase [].
Centrosome and spindle pole associated protein 1 (CSPP) interacts with MyoGEF (a guanine nucleotide exchange factor that localises to the central spindle and cleavage furrow) and may play a role in cell-cycle-dependent microtubule organisation [
,
].
Glycine/sarcosine/betaine reductase complex, protein C, alpha subunit
Type:
Family
Description:
This group represents a glycine/sarcosine/betaine reductase complex, component C, alpha subunit. Please see the following relevant references: [
,
,
].
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases [
]. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [,
]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). DOCK2 is a hematopoietic cell-specific, class A DOCK and is an atypical guanine nucleotide exchange factor (GEF) that lacks the conventional Dbl homology (DH) domain. It plays an important role in lymphocyte migration and activation, T-cell differentiation, neutrophil chemotaxis, and type I interferon induction [
,
,
].This entry represents the DHR-2 domain of DOCK2, which contains the catalytic GEF activity for Rac. Class A DOCKs, like DOCK2, are specific GEFs for Rac. DOCK2 then activates RAC1 and RAC2, but not CDC42. It may also participate in IL2 transcriptional activation via the activation of RAC2 [
].
Lymphocyte Antigen 6 (Ly-6) superfamily members are cysteine-rich, generally GPI-anchored cell surface proteins with known or putative roles in immune function. Ly6G5b is a member of the family. It is a potentially secreted protein of unknown function [
].
Ras association domain-containing protein 4, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [].RASSF4 is one of the C-terminal (also known as classical) RASSF proteins, characterised by an RA domain and a SARAH domain (
) in the C terminus. There is conflicting evidence for the function of RASSF4. It is variously reported to have tumour suppressor characteristics [
,
,
], and to have a function in promoting cell proliferation [].This entry represents the Ras-associating (RA) domain of RASSF4, which has a β-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases.
Ras association domain-containing protein 5, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF5 is one of the C-terminal (also known as classical) RASSF proteins, characterised by an RA domain and a SARAH domain (
) in the C terminus. RASSF5 is also referred to as NORE1 or RAPL, and is known to exist as at least three transcripts. RASSF5 is primarily involved in the control of apoptosis, through involvement in a number of different apoptosis pathways [
,
], and functions as a tumour suppressor []. One transcript (A) has been suggested to be involved in developing the nervous system []. It has also been reported that RASSF5 is involved in the regulation of p27 localisation []. This entry represents the Ras-associating (RA) domain of RASSF5, which has a β-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases.
Ras association domain-containing protein 7, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF7 is one of the N-terminal RASSF proteins, characterised by an RA domain in the N terminus. It was previously known as HRC1 (HRAS1-related cluster protein 1), and is predicted to exist as at least three isoforms as a result of alternative splicing [
]. RASSF7 has been shown to promote mitosis through the regulation of spindle formation []. There is conflicting evidence on the methylation of the RASSF7 promoter, and subsequently on the status of RASSF7 as a tumour suppressor [,
].This entry represents the as-associating (RA) domain of RASSF7.
Ras association domain-containing protein 9, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF9 is one of the N-terminal RASSF proteins, characterised by an RA domain in the N terminus. It was previously called P-CIP1 (peptidylglycine alpha-amidating monooxygenase (PAM) COOH-terminal interactor protein-1), and was believed to play a role in the regulation of PAM in endosomal pathways [
]. Very little else is known about the function of RASSF9, but it has been suggested to be involved in epidermal homeostasis [].This entry represents the as-associating (RA) domain of RASSF9.
Ras association domain-containing protein 10, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF10 is one of the N-terminal RASSF proteins, characterised by an RA domain in the N terminus. It is expressed in a range of tissues, and has been shown to function as a tumour suppressor in a number of studies [
,
].This entry represents the as-associating (RA) domain of RASSF10.
Grb7 (growth factor receptor bound protein 7) is an adapter protein mediating signal transduction from multiple cell surface receptors to diverse downstream pathways [
,
,
]. It contains a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region and a C-terminal SH2 domain [,
]. This entry represents the Ras-associating (RA) domain of Grb7.
Ras association domain-containing protein 1, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF1 is one of the C-terminal (also known as classical) RASSF proteins, characterised by an RA domain and a SARAH domain () in the C terminus [
]. Human RASSF1 has multiple transcripts as a result of alternative splicing and differential promoter usage. RASSF1A and 1C are the most widely studied and characterised of these. While they are both involved in regulation of growth and migration via microtubule localization, they have very different biological properties [].RASSF1A is a tumour suppressor primarily important in microtubule stability, but implicated in a number of different functions, including cell-cycle regulation, spindle assembly, chromosome attachment, apoptosis and inflammation control, amongst others [
].In contrast, RASSF1C has not been shown to be a tumour suppressor, and has even been implicated as an oncogene by a number of mechanisms [
]. It has been reported to activate cell proliferation through interaction with IGFBP-5, and may also interact with TFPI-2, which is involved in angiogenesis and tumour growth/metastasis [,
]. RASSF1C has also been reported to interact with and stabilise microtubules [].This entry represents the Ras-associating (RA) domain of RASSF1, which has a β-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases.
Ras association domain-containing protein 2, RA domain
Type:
Domain
Description:
The Ras association domain (RASSF) proteins are named due to the presence of a Ras association (RA) domain in their N or C terminus that can potentially interact with the Ras GTPase family of proteins. These GTPases control a variety of cellular processes, such as membrane trafficking, apoptosis, and proliferation. RASSF proteins contain several other functional domains that modulate associations with other proteins. RASSF proteins with the RA domain at the C terminus (which are termed C-terminal or classical RASSF) usually also include a Salvador-RASSF-Hippo (SARAH) domain involved in several protein-protein interactions and for homo- and heterodimerisation of RASSF isoforms. N-terminal RASSF proteins (with the RA domain in the N terminus) do not usually contain a SARAH domain [
].At least 10 RASSF family members have been characterised (with multiple splice variants), many of which have been shown to play a role in tumour suppression. RASSF proteins also act as scaffolding agents in microtubule stability, regulate mitotic cell division, control cell migration and cell adhesion, and modulate NF-KB activity and the duration of inflammation. Loss of RASSF expression through promoter methylation has been shown in numerous types of cancer, including leukemia, melanoma, breast and prostate cancer [
].RASSF2 is one of the C-terminal (also known as classical) RASSF proteins, characterised by an RA domain and a SARAH domain (
) in the C terminus. It is primarily a nuclear protein existing in two major isoforms, A and C, which has been implicated in tumourigenesis and in regulation of cell cycle and apoptosis [
,
].This entry represents the Ras-associating (RA) domain of RASSF2, which has a β-grasp ubiquitin-like fold with low sequence similarity to ubiquitin. The RA domain mediates interactions with Ras and other small GTPases.
Protein of unknown function DUF1780, putative endonuclease
Type:
Family
Description:
This is a family of uncharacterised proteins. The structure of a hypothetical protein from Pseudomonas aeruginosa has shown it to adopt an α/β fold, placing it in the Endonuclease superfamily/clan of restriction endonucleases.
Anti sigma-E protein RseA, N-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Sigma-E is important for the induction of proteins involved in heat shock response. RseA binds sigma-E via its N-terminal domain, sequestering sigma-E and preventing transcription from heat-shock promoters [
]. The C-terminal domain is located in the periplasm, and may interact with other protein that signal periplasmic stress.The structure of the RseA N-terminal domain presents a four helices fold.
Protein translocase subunit SecA 2, Bacillus anthracis-type
Type:
Family
Description:
In bacteria, the majority of exported proteins are transported by the general Sec pathway from their site of synthesis in the cytoplasm across the cytoplasmic membrane. The ATPase SecA powers this Sec-mediated export [
]. Members of this family always occur in genomes with the preprotein translocase SecA () and closely resemble it, hence the designation SecA2. However, this appears to be a different type of accessory Sec system SecA2 from the serine-rich glycoprotein type found in Staphylococcus and Streptococcus (
), and the actinobacterial SecA2 (
). This type occurs in species such as Bacillus anthracis, Geobacillus thermoglucosidasius, Solibacillus silvestris, etc [
].
This entry represents the human Cat eye syndrome critical region protein 6 (also known as transmembrane protein 121B) and its homologues [
,
]. Cat Eye Syndrome (CES) is characterised clinically by the combination of coloboma of the iris and anal atresia with fistula. CES is a rare condition caused by the duplication of a 2 Mb region of human 22q11.2 resulting in four copies of the region rather than the usual two copies [].
High mobility group nucleosome-binding domain-containing protein 5
Type:
Family
Description:
HMGN5, also known as NBP-45, binds to nucleosomes via its nucleosomal binding domain (NBD), unfolds chromatin, and affects transcription [
]. It binds preferentially to euchromatin and modulates the fidelity of the cellular transcription by counteracting linker histone-mediated chromatin compaction [].
Heat shock 70kDa protein 12A, nucleotide-binding domain
Type:
Domain
Description:
Heat shock 70kDa protein 12A (HS12A) is an adapter protein for the amyloid precursor protein receptor SorLA [
]. As a member of the heat shock protein 70 (HSP70) family of chaperones, HS12A shows a nucleotide-binding domain (NBD, this entry) and a substrate-binding domain (SBD). The nucleotide sits in a deep cleft formed between the two lobes of the NBD. It is predominantly expressed in neuronal cells. and may play a role in the atherosclerotic process []. Mutations in this protein have been related to both schizophrenia and bipolar affective disorder [].
Salmonella surface presentation of antigen M protein
Type:
Family
Description:
The Salmonella typhimurium Surface Presentation of Antigens M gene (SpaM)
is one of 12 that form a cluster responsible for invasion properties [].The gene product is required for entry by the bacterium into epithelial
cells, and is thus considered to be a virulence factor []. Other Spa genes in the cluster are related to invasion (Inv) genes in similar Salmonella
and Shigella species [], and flagella biosynthesis genes in Helicobacter pylori [].A homologue of this protein has been found recently in Salmonella enterica
[]. The protein, named InvI, is required by the organism to gain access tomammalian epithelial cells, and cellular mutants (InvI-) failed to
successfully infect these cells. It has also been found that the inv-spa loci of this particular species encode for a type III protein secretion
system, essential in the bacterium's host cell invasion process [].
Lateral signaling target protein 2 (Lst2) is a monoubiquitinylated phosphoprotein that functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling. Unlike other FYVE domain-containing proteins, Lst2 displays primarily non-endosomal localization. Its endosomal localization is regulated by monoubiquitinylation. Lst2 physically binds Trim3, also known as BERP or RNF22, which is a coordinator of endosomal trafficking and interacts with Hrs and a complex that biases cargo recycling [].This entry represents the FYVE domain of Lst2.
Stretch-activated cation channel Mid1/Calcium influx-promoting protein Ehs1
Type:
Family
Description:
In Saccharomyces cerevisiae, Mid1 is a yeast plasma membrane protein required for Ca2+ influx induced by the mating pheromone alpha-factor during the mating process [
,
,
]. The protein is composed of 548-amino-acid residues, contains four hydrophobic regions (H1, H2, H3 and H4) and two cysteine-rich regions (C1 and C2) at the C terminus. H1 appears to be a signal sequence necessary for the alpha-factor-induced delivery to the plasma membrane. The region from H1 to H3 is required for the localisation of Mid1 in the plasma and ER membranes. C1 and C2 are thought to be involved in oligomerisation via the formation of disulphide bonds. Trafficking of Mid1-GFP to the plasma membrane is dependent on the N-glycosylation of Mid1 and the transporter protein Sec12. This suggests that the trafficking of Mid1-GFP to the plasma membrane requires a Sec12-dependent pathway from the ER to the Golgi, and that Mid1 is recruited via a Sec6- and Sec7-independent pathway from the Golgi to the plasma membrane.
This entry also includes Ehs1 from Schizosaccharomyces pombe. Ehs1 is required for Ca2+ influx and for vitality of cells in a late, pheromone-induced event of the mating process requiring calcium-induced signaling [
].
Uncharacterised conserved protein UCP01524, polysaccharide biosynthesis aminopeptidase-like
Type:
Family
Description:
The proteins in this entry are encoded by genes located in polysaccharide biosynthesis gene clusters, and are therefore believed to be involved in polysaccharide biosynthesis. The
stegene cluster (for
Streptomyces
eps) is involved in exopolysaccharide EPS 139A biosynthesis in Streptomyces sp. 139 [
].Members of this group exhibit distant sequence similarity to aminopeptidases (
, MEROPS peptidase family M28).
Uncharacterised conserved protein UCP014405, metallopeptidase Zn-binding site
Type:
Family
Description:
Members of this family contain a characteristic pattern of the Zn-binding site of neutral zinc metallopeptidases. Members of this family have not been characterised.
BTB/POZ domain-containing protein 8, BTB/POZ domain 1
Type:
Domain
Description:
BTB/POZ domain-containing protein 8 (also known as AP2-interacting clathrin-endocytosis protein (APache)), is involved in synaptic vesicle trafficking, neuronal development, and synaptic plasticity [].This entry represents the first BTB (Broad-Complex, Tramtrack and Bric a brac)/POZ (poxvirus and zinc finger) domain found in BTBD8,
DOCK family members are evolutionarily conserved guanine nucleotide exchange factors (GEFs) for Rho-family GTPases [
]. DOCK proteins are required during several cellular processes, such as cell motility and phagocytosis. The N-terminal SH3 domain of the DOCK proteins functions as an inhibitor of GEF, which can be relieved upon its binding to the ELMO1-3 adaptor proteins, after their binding to active RhoG at the plasma membrane [,
]. DOCK family proteins are categorised into four subfamilies based on their sequence homology: DOCK-A subfamily (DOCK1/180, 2, 5), DOCK-B subfamily (DOCK3, 4), DOCK-C subfamily (DOCK6, 7, 8), DOCK-D subfamily (DOCK9, 10, 11) []. All DOCKs contain two homology domains: the DHR-1 (Dock homology region-1), also called CZH1 (CED-5, Dock180, and MBC-zizimin homology 1), and DHR-2 (also called CZH2 or Docker). DOCK3, also called modifier of cell adhesion (MOCA), is an atypical guanine nucleotide exchange factor (GEF) that lacks the conventional Dbl homology (DH) domain. DOCK3 is a specific GEF for Rac. It regulates N-cadherin dependent cell-cell adhesion, cell polarity, and neuronal morphology. It promotes axonal growth by stimulating actin polymerization and microtubule assembly [
,
]. DOCK3 is linked to Alzheimer disease due to its interaction with presenilin proteins and ability to stimulate Tau/MAPT phosphorylation [].This entry represents the DHR-2 domain of DOCK3, which contains the catalytic GEF activity for Rac [
].
Insulin-like growth factor-binding protein family 1-6, chordata
Type:
Family
Description:
Insulin-like growth factors (IGFs)-I and -II are small secreted peptides that stimulate the survival, and promote the proliferation and differentiation, of many cell types [
]. In biological fluids, these growth factors are usually bound to IGF-binding proteins (IGFBPs), which regulate their availability and activity by prolonging their half-life and modulating their receptor interactions. To date, six IGFBP family members have been identified (termed IGFBP1-6) [
]. They share a conserved gene (intron-exon) organisation and high IGF-binding affinity. Structurally, the proteins also share a common domain architecture, possessing a conserved N-terminal IGFBP domain, a highly variable mid-section, and a thyroglobulin type-1 (Tg1) domain in their C-terminal regions. In addition to their role in the regulation of IGF activity, there is evidence for the direct association of IGFBPs with a variety of extracellular and cell surface molecules [
,
], with consequent effects upon important biological processes. These include modulation of bone cell proliferation [], and growth arrest of breast and prostate cancer cells [,
].
Glucan-binding protein C/Surface antigen I/II, V-domain superfamily
Type:
Homologous_superfamily
Description:
This domain superfamily is found in glucan-binding protein C (GbpC) and in the V-region of surface protein antigen; both these proteins belong to the Spa family of Streptococcal proteins [
]. This domain consists of a β-supersandwich of 18 β-strands in two sheets. There are at least four types of glucan-binding proteins (Gbp) in Streptococcus mutans, GbpA, GbpB, GbpC and GbpD. These proteins promote the adhesion of Streptococcal bacteria to teeth and are associated with dental caries [
]. GbpC is a cell-wall anchoring protein that plays an important role in sucrose-dependent adhesion by binding to soluble glucan synthesised by glucosyltransferase D (GTFD) [].Spa antigens I/II are multi-functional proteins expressed at the cell wall surface of oral Streptococci, where they function as adhesins. Antigens I/II recognise a wide range of ligands. They exert an immunomodulatory effect on human cells and are important in inflammatory disorders, such as dental caries. These proteins can be divided into seven regions: signal peptide, N-terminal, A-region (alanine-rich), V-region (variable domain), P-region (proline-rich), C-terminal domain, and a cell wall anchor motif. The V-region is the central domain and exhibits the greatest variability in sequence, and is responsible for binding monocyte receptors, its binding stimulating the release of TNF-alpha from the monocytes. The crystal structure of the V-region revealed a lectin-like fold that displays a putative preformed carbohydrate-binding site stabilised by a metal ion [
].
Putative type 4B encapsulin shell protein superfamily
Type:
Homologous_superfamily
Description:
Proteins in this entry may be the encapsulin shell protein in a type 4 A-domain encapsulin nanocompartment system. Its cargo may be upstream glyceraldehyde-3-phosphate dehydrogenase [
]. It has been shown that bacterial/archaeal encapsulin-like systems and HK97-type viruses share a common ancestor and it is likely that encapsulins have evolved from HK97-type phages.
This entry represents the RNA recognition motif 2 (RRM2) of RBM47.RBM47 is a putative RNA-binding protein that shows high sequence homology with heterogeneous nuclear ribonucleoprotein R (hnRNP R) and heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Like hnRNP R and hnRNP Q, RBM47 contains two well-defined and one degenerated RNA recognition motifs (RRMs). RBM47 is necessary for Cytidine to Uridine RNA editing [
,
].
This entry represents the RNA recognition motif 3 (RRM3) of RBM47.RBM47 is a putative RNA-binding protein that shows high sequence homology with heterogeneous nuclear ribonucleoprotein R (hnRNP R) and heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Like hnRNP R and hnRNP Q, RBM47 contains two well-defined and one degenerated RNA recognition motifs (RRMs). RBM47 is necessary for Cytidine to Uridine RNA editing [
,
].
Ribosome biogenesis protein 15, RNA recognition motif
Type:
Domain
Description:
This entry represents the RNA recognition motif (RRM) of Nop15. Nop15 has been identified as a component of a pre-60S particle. It interacts with RNA components of the early pre-60S particles. Furthermore, Nop15 binds directly to a pre-rRNA transcript in vitro and is required for pre-rRNA processing. It functions as a ribosome synthesis factor required for the 5' to 3' exonuclease digestion that generates the 5' end of the major, short form of the 5.8S rRNA as well as for processing of 27SB to 7S pre-rRNA. Nop15p also play a specific role in cell cycle progression [
]. Nop15p contains an RNA recognition motif (RRM).
RNA-binding protein fusilli, RNA recognition motif 2
Type:
Domain
Description:
This entry represents the RNA recognition motif 2 (RRM2) of RNA-binding protein Fusilli.Fusilli is encoded by Drosophila fusilli (fus) gene. Loss of Fusilli activity causes lethality during embryogenesis in flies. Drosophila Fusilli can regulate endogenous fibroblast growth factor receptor 2 (FGFR2) splicing and functions as a splicing factor []. Fusilli contains three RNA recognition motifs (RRMs), an N-terminal domain with unknown function and a C-terminal domain particularly rich in alanine, glutamine, and serine.
This entry represents the RNA recognition motif 1 (RRM1) of RNA-binding protein 5.RNA-binding protein 5 (RBM5), also known as LUCA15, is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, c-FLIP [
] and caspase 2 []. In the case of FAS, it promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis [,
]. In the case of CASP2/caspase-2, it promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis [].
This entry represents the RNA recognition motif 2 (RRM2) of RNA-binding protein 10.RBM10, also known as S1-1, is a nuclear RNA-binding protein with domains characteristic of RNA processing proteins. Similar to RBM5, it promotes exon skipping of Fas pre-mRNA as well as selection of an internal 5'-splice site in Bcl-x pre-mRNA [
]. It preferentially binds to G- and U-rich RNA sequences [].
This entry represents the RNA recognition motif 2 (RRM2) of RNA-binding protein 5.RNA-binding protein 5 (RBM5), also known as LUCA15, is a component of complexes involved in 3' splice site recognition and regulates alternative splicing of apoptosis-related genes, including the Fas receptor, c-FLIP [
] and caspase 2 []. In the case of FAS, it promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis [,
]. In the case of CASP2/caspase-2, it promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis [].
RBM47 is a putative RNA-binding protein that shows high sequence homology with heterogeneous nuclear ribonucleoprotein R (hnRNP R) and heterogeneous nuclear ribonucleoprotein Q (hnRNP Q). Like hnRNP R and hnRNP Q, RBM47 contains two well-defined and one degenerated RNA recognition motifs (RRMs). RBM47 is necessary for Cytidine to Uridine RNA editing [
,
].This entry represents the RNA recognition motif 1 (RRM1) of RBM47.
This entry represents the RRM4 of RBM12B which contains five distinct RNA binding motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains) [
,
,
]. Its biological role remains unclear.
This entry represents the RNA recognition motif 2 of DAZAP1.DAZAP1, initially identified as a binding partner of Deleted in Azoospermia (DAZ), is a multi-functional ubiquitous RNA-binding protein expressed most abundantly in the testis and is essential for normal cell growth, development, and spermatogenesis [
,
]. DAZAP1 is a shuttling protein whose acetylated form is predominantly nuclear and the nonacetylated form is in cytoplasm []. DAZAP1 also functions as a translational regulator that activates translation in an mRNA-specific manner []. It also interacts with numerous hnRNPs, including hnRNP U, hnRNP U like-1, hnRNPA1, hnRNPA/B, and hnRNP D, suggesting DAZAP1 might associate and cooperate with hnRNP particles to regulate adenylate-uridylate-rich elements (AU-rich element or ARE)-containing mRNAs [
,
]. DAZAP1 contains two N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), and a C-terminal proline-rich domain [].This entry also includes the orthologue from Drosophila melanogaster Heterogeneous nuclear ribonucleoprotein 27C (Rbp7).
This entry represents the RNA recognition motif 1 of DAZAP1.DAZAP1, initially identified as a binding partner of Deleted in Azoospermia (DAZ), is a multi-functional ubiquitous RNA-binding protein expressed most abundantly in the testis and is essential for normal cell growth, development, and spermatogenesis [
,
]. DAZAP1 is a shuttling protein whose acetylated form is predominantly nuclear and the nonacetylated form is in cytoplasm []. DAZAP1 also functions as a translational regulator that activates translation in an mRNA-specific manner []. It also interacts with numerous hnRNPs, including hnRNP U, hnRNP U like-1, hnRNPA1, hnRNPA/B, and hnRNP D, suggesting DAZAP1 might associate and cooperate with hnRNP particles to regulate adenylate-uridylate-rich elements (AU-rich element or ARE)-containing mRNAs [,
]. DAZAP1 contains two N-terminal RNA recognition motifs (RRMs), also termed RBDs (RNA binding domains) or RNPs (ribonucleoprotein domains), and a C-terminal proline-rich domain [].
DNA-dependent protein kinase catalytic subunit, catalytic domain
Type:
Domain
Description:
This entry represents the catalytic domain of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). The DNA-PK complex is composed of DNA-PKcs, the heterodimer Ku70/80, XRCC4, and ligase IV. The DNA-PK complex is involved in non-homologous end joining (NHEJ), a process of repairing double strand breaks (DSBs) by joining together two free DNA ends of little homology [
].
Haemagglutinin outer capsid protein VP4, concanavalin-like domain
Type:
Domain
Description:
The rotavirus outer capsid consists of the coat glycoprotein VP7 and the spike protein VP4. VP4 functions in cell attachment and membrane penetration. VP4 is cleaved by the host's trypsin-like proteases to produce two fragments, VP5 and VP8. VP8 functions as a viral haemagglutinin to bind sialic acid receptors on host cell membranes, while VP5 is a membrane penetration protein [
]. The haemagglutinin domain has a β-sandwich fold similar to that of the sugar-binding galectins family of proteins [,
]. The receptor-binding specificity of rotaviruses by VP4 may be influenced by the VP7 protein.This entry represents the N-terminal concanavalin-like domain from the VP4 protein of rotavirus.
Heat shock protein DnaJ, cysteine-rich domain superfamily
Type:
Homologous_superfamily
Description:
The hsp70 chaperone machine performs many diverse roles in the cell, including folding of nascent proteins, translocation of polypeptides across organelle membranes, coordinating responses to stress, and targeting selected proteins for degradation. DnaJ is a member of the hsp40 family of molecular chaperones, which is also called the J-protein family, the members of which regulate the activity of hsp70s. DnaJ (hsp40) binds to DnaK (hsp70) and stimulates its ATPase activity, generating the ADP-bound state of DnaK, which interacts stably with the polypeptide substrate [
]. Besides stimulating the ATPase activity of DnaK through its J-domain, DnaJ also associates with unfolded polypeptide chains and prevents their aggregation [].DnaJ consists of an N-terminal conserved domain (called 'J' domain) of about 70 amino acid residues, a glycine and phenylalanine-rich domain ('G/F' domain), a central cysteine rich domain (CR-type zinc finger) containing four repeats of a CXXCXGXG motif which can coordinate two zinc atom and a C-terminal domain (CTD) [
].This entry represents the central cysteine-rich (CR) domain of DnaJ proteins. This central cysteine rich domain (CR-type zinc finger) has an overall V-shaped extended β-hairpin topology and contains four repeats of the motif CXXCXGXG where X is any amino acid. The isolated cysteine rich domain folds in zinc dependent fashion. Each set of two repeats binds one unit of zinc. Although this domain has been implicated in substrate binding, no evidence of specific interaction between the isolated DnaJ cysteine rich domain and various hydrophobic peptides has been found [
].
Conserved hypothetical protein CHP02587, putative integral membrane
Type:
Family
Description:
Members of this protein family are found in Anabaena sp. (strain PCC 7120), Agrobacterium tumefaciens, Rhizobium meliloti, and Gloeobacter violaceus in a conserved two-gene neighbourhood. The proteins appear to span the membrane seven times.
Protein kinases C (PKCs) constitute a family of Ser/Thr kinases. PKCs are classified into three groups (classical, atypical, and novel) depending on their mode of activation and the structural characteristics of their regulatory domain [
,
]. Novel PKCs (nPKCs) comprise delta, epsilon, eta, and theta isoforms, which have tandem C1 domains and a C2 domain that does not bind calcium []. nPKCs are calcium-independent, but require DAG (1,2-diacylglycerol) and phosphatidylserine (PS) for activity. PKC-theta is selectively expressed in T-cells and plays an important and non-redundant role in several aspects of T-cell biology [
]. Although T-cells also express other PKC isoforms, PKC-theta is unique in that upon antigen stimulation, it is translocated to the plasma membrane at the immunological synapse, where it mediates signals essential for T-cell activation []. It is essential for TCR-induced proliferation, cytokine production, T-cell survival, and the differentiation and effector function of T-helper (Th) cells, particularly Th2 and Th17. PKC-theta is being developed as a therapeutic target for Th2-mediated allergic inflammation and Th17-mediated autoimmune diseases [
].
Calcium/calmodulin-dependent protein kinase type 1B, catalytic domain
Type:
Domain
Description:
Serine/Threonine kinases (STKs) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. CaMKs are multifunctional calcium and calmodulin (CaM) stimulated STKs involved in cell cycle regulation [
]. The CaMK family includes CaMKI, CaMKII, CaMKIV, and CaMK kinase (CaMKK) []. In vertebrates, there are four CaMKI proteins encoded by different genes (alpha, beta, gamma, and delta), each producing at least one variant. CaMKs contain an N-terminal catalytic domain and a C-terminal regulatory domain that harbors a CaM binding site. CaMKI proteins are monomeric and they play pivotal roles in the nervous system, including long-term potentiation, dendritic arborization, neurite outgrowth, and the formation of spines, synapses, and axons [,
]. The CaMKI-beta subfamily is part of a larger superfamily that includes the catalytic domains of other protein kinases, RIO kinases, aminoglycoside phosphotransferase, choline kinase, and phosphoinositide 3-kinase.
Severe acute respiratory syndrome coronavirus 3b protein
Type:
Family
Description:
This family contains the SARS coronavirus 3b protein which is predominantly localized in the nucleolus, and induces G0/G1 arrest and apoptosis in transfected cells [
,
]. SARS-CoV mRNA 3 encodes the distinct proteins ORF3a and ORF3b proteins, which are translated in different reading frames. SARS-CoV accessory protein ORF3b antagonizes interferon (IFN) function by modulating the activity of IFN regulatory factor 3 (IRF3). The IFN system functions as the first line of defense against viral infection in mammalian cells. Viral infection triggers a series of cellular events that lead to the production of IFN and several downstream antiviral genes, helping to establish an antiviral state. Viruses encode IFN antagonists to counteract the antiviral effects of IFN. SARS-CoV ORF3b, ORF6, and N proteins function as IFN antagonists. ORF3b inhibits both IFN synthesis and signaling [,
]. It localizes to the nucleus in transfected cells [].
Actin-related protein 2/3 complex subunit 3 superfamily
Type:
Homologous_superfamily
Description:
Arp2/3 binds to pre-existing actin filaments and nucleates new daughter filaments, and thus becomes incorporated into the dynamic actin network at the leading edge of motile cells and other actin-based protrusive structures [
]. In order to nucleate filaments, Arp2/3 must bind to a member of the N-WASp/SCAR family protein []. Arp2 and Arp3 are thought to be brought together after activation, forming an actin-like nucleus for actin monomers to bind and create a new actin filament. In the absence of an activating protein, Arp2/3 shows very little nucleation activity. Recent research has focused on the binding and hydrolysis of ATP by Arp2 and Arp3 [], and crystal structures of the Arp2/3 complex have been solved [].The human complex consists of Arp2/3 complex composed of ARP2, ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. This superfamily represents the ARPC3/p21-ARC subunit. This subunit is composed of five helices, where one helix is surrounded by the others.
Actin-related protein 2/3 complex subunit 5 superfamily
Type:
Homologous_superfamily
Description:
Arp2/3 binds to pre-existing actin filaments and nucleates new daughter filaments, and thus becomes incorporated into the dynamic actin network at the leading edge of motile cells and other actin-based protrusive structures [
]. In order to nucleate filaments, Arp2/3 must bind to a member of the N-WASp/SCAR family protein []. Arp2 and Arp3 are thought to be brought together after activation, forming an actin-like nucleus for actin monomers to bind and create a new actin filament. In the absence of an activating protein, Arp2/3 shows very little nucleation activity. Recent research has focused on the binding and hydrolysis of ATP by Arp2 and Arp3 [], and crystal structures of the Arp2/3 complex have been solved [].The human Arp2/3 complex consists of ARP2, ARP3, ARPC1B/p41-ARC, ARPC2/p34-ARC, ARPC3/p21-ARC, ARPC4/p20-ARC and ARPC5/p16-ARC. This superfamily represents the ARPC5/p16-ARC subunit. This subunit has a multihelical structure composed of two (curved) layers: alpha/alpha and a right-handed superhelix.
Ran-GTPase activating protein 1, C-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Ran GTPase is a ubiquitous protein required for nuclear transport, spindle assembly, nuclear assembly and mitotic cell cycle regulation. RanGTPase activating protein 1 (RanGAP1) is one of several RanGTPase accessory proteins. During interphase, RanGAP1 is located in the cytoplasm, while during mitosis it becomes associated with the kinetochores [
]. Cytoplasmic RanGAP1 is required for RanGTPase-directed nuclear transport. The activity of RanGAP1 requires the accessory protein RanBP1. RanBP1 facilitates RanGAP1 hydrolysis of Ran-GTP, both directly and by promoting the dissociation of Ran-GTP from transport receptors, which would otherwise block RanGAP1-mediated hydrolysis. RanGAP1 is thought to bind to the Switch 1 and Switch 2 regions of RanGTPase. The Switch 2 region can be buried in complexes with karyopherin-beta2, and requires the interaction with RanBP1 to permit RanGAP1 function. RanGAP1 can undergo SUMO (small ubiquitin-like modifier) modification, which targets RanGAP1 to RanBP2/Nup358 in the nuclear pore complex, and is required for association with the nuclear pore complex and for nuclear transport []. The enzymes involved in SUMO modification are located on the filaments of the nuclear pore complex.The RanGAP1 N-terminal domain is fairly well conserved between vertebrate and fungal proteins, but yeast does not contain the C-terminal domain. The C-terminal domain is SUMO-modified and required for the localisation of RanGAP1 at the nuclear pore complex. The structure of the C-terminal domain is multihelical, consisting of two curved alpha/alpha layers in a right-handed superhelix.
Non-homologous end joining protein Ku, prokaryotic type
Type:
Family
Description:
This superfamily consists of prokaryotic Ku domain containing proteins. In the eukaryotes it has been shown that the Ku protein is involved in repairing DNA double-strand breaks by non-homologous end-joining [
,
]. The Ku protein is a heterodimer of approximately 70kDa and 80kDa subunits []. Both these subunits have strong sequence similarity and it has been suggested that they may have evolved by gene duplication from a homodimeric ancestor in eukaryotes []. The prokaryotic Ku members are homodimers and they have been predicted to be involved in the DNA repair system, which is mechanistically similar to eukaryotic non-homologous end joining [,
]. Recent findings have implicated yeast Ku in telomeric structure maintenance in addition to on-homologous end-joining. Some of the phenotypes of the Ku-knockout mice may indicate a similar role for Ku at mammalian telomeres [].Evolutionary notes: With current available phyletic information it is difficult to determine the correct evolutionary trajectory of the Ku domain. It is possible that the core Ku domain was present in bacteria and archaea even before the presence of the eukaryotes. Eukaryotes might have vertically inherited the Ku-core protein, from a common ancestor shared with a certain archaeal lineage or through horizontal transfer from bacteria. Alternatively, the core Ku domain could have evolved in the eukaryotic lineage and then horizontally transferred to the prokaryotes. Sequencing of additional archaeal genomes and those of early-branching eukaryotes may help resolving the evolutionary history of the Ku domain.Structure notes: The eukaryotic Ku heterodimer comprises an alpha/beta N-terminal, a central β-barrel domain and a helical C-terminal arm [
]. Structural analysis of the Ku70/80 heterodimer bound to DNA indicate that subunit contacts lead to the formation of a highly charged channel through which the DNA passes without making any contacts with the DNA bases [].For additional information please see [
].
Ribosome maturation protein SBDS, N-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Proteins containing this domain are highly conserved in species ranging from archaea to vertebrates and plants [
], including several Shwachman-Bodian-Diamond syndrome (SBDS, OMIM 260400) proteins from both mouse and humans. Shwachman-Diamond syndrome is an autosomal recessive disorder with clinical features that include pancreatic exocrine insufficiency, haematological dysfunction and skeletal abnormalities. It is characterised by bone marrow failure and leukemia predisposition. Members of this superfamily play a role in RNA metabolism [,
]. In yeast Sdo1 is involved in the biogenesis of the 60S ribosomal subunit and translational activation of ribosomes. Together with the EF-2-like GTPase RIA1 (EfI1), it triggers the GTP-dependent release of TIF6 from 60S pre-ribosomes in the cytoplasm, thereby activating ribosomes for translation competence by allowing 80S ribosome assembly and facilitating TIF6 recycling to the nucleus, where it is required for 60S rRNA processing and nuclear export. This data links defective late 60S subunit maturation to an inherited bone marrow failure syndrome associated with leukemia predisposition [].A number of uncharacterised hydrophilic proteins of about 30kDa share regions of similarity. These include,Mouse protein 22A3.Saccharomyces cerevisiae chromosome XII hypothetical protein YLR022c.Caenorhabditis elegans hypothetical protein W06E11.4.Methanocaldococcus jannaschii (Methanococcus jannaschii) hypothetical protein MJ0592.
DNA damage inducible protein 1 ubiquitin-like domain
Type:
Domain
Description:
DDI1 (DNA damage inducible protein 1) has an amino-terminal ubiquitin-like domain, an retroviral protease-like (RVP-like) domain, and a UBA (ubiquitin-associated) domain. This entry represents the amino-terminal ubiquitin-like domain of DDI1 [
,
,
].Ubiquitin is a globular protein, the last four C-terminal residues (Leu-Arg-Gly-Gly) extending from the compact structure to form a 'tail', important for its function. The latter is mediated by the covalent conjugation of ubiquitin to target proteins, by an isopeptide linkage between the C-terminal glycine and the epsilon amino group of lysine residues in the target proteins.
Members of this family are found exclusively in type III secretion apparatus gene clusters in bacteria. Those bacteria with a protein from this family tend to target animal cells, as does Yersinia pestis [
]. This protein is small (about 70 amino acids) and not well characterised.
Trafficking protein particle complex II-specific subunit 65
Type:
Family
Description:
Trs65 is a specific subunit of the TRAPP II complex, a highly conserved vesicle tethering complex that functions in the late Golgi as a guanine nucleotide exchanger (GEF) for the Golgi YPT1 GTPase [
,
]. TRAPP subunits are found in two different sized complexes, TRAPP I and TRAPP II. While both complexes contain the same seven subunits, Bet3p, Bet5p, Trs20p, Trs23p, Trs31p, Trs33p and Trs85p, with TRAPPC human equivalents, TRAPP II has the additional three subunits ,Trs65p, Trs120p and Trs130p [
].
Chromosome passenger complex (CPC) protein INCENP N-terminal
Type:
Domain
Description:
This domain family is found in eukaryotes, and is approximately 40 amino acids in length. INCENP is a regulatory protein in the chromosome passenger complex. It is involved in regulation of the catalytic protein Aurora B. It performs this function in association with two other proteins - Survivin and Borealin. These proteins form a tight three-helical bundle. The N-terminal domain is the domain involved in formation of this three helical bundle.
Ribosomal protein L30, ferredoxin-like fold domain superfamily
Type:
Homologous_superfamily
Description:
Ribosomal protein L30 is one of the proteins from the large ribosomal subunit. L30 belongs to a family of ribosomal proteins which, on the basis of sequence similarities [
], groups bacteria and archaea L30, yeast mitochondrial L33, and Drosophila melanogaster, Dictyostelium discoideum (Slime mold), fungal and mammalian L7 ribosomal proteins. L30 from bacteria are small proteins of about 60 residues, those from archaea are proteins of about 150 residues, and eukaryotic L7 are proteins of about 250 to 270 residues.This entry represents a domain superfamily with a ferredoxin-like fold, with a core structure consisting of core: beta-α-β-α-β. This domain is found in prokaryotic ribosomal protein L30 (short-chain member of the family), as well as in archaeal L30 (L30a) (long-chain member of the family), the later containing an additional C-terminal (sub)domain).It is also found in nucleolar proteins with similarity to large ribosomal subunit L7 proteins. These are constituents of 66S pre-ribosomal particles and play an essential role in processing of precursors to the large ribosomal subunit RNAs [
,
,
].
This is the N-terminal region of GspC proteins, which is part of the Type II secretion system. The region is made up of a short N-terminal cytoplasmic domain that is followed by the single transmembrane helix, a Pro-rich linker, and the so-called homology region domain in the periplasm. This inner membrane GspC interacts with the outer membrane secretin GspD via periplasmic domains, an interaction which is critical for the effectiveness of type II secretion [
]. This domain can also be found in GspN from Pseudomonas aeruginosa. The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space [
]. T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK []. GspD has been shown to interact with the inner membrane component GspC []. The T2SS pseudopilus is a periplasmic filament composed of the major pseudopilin, EpsG, and four minor pseudopilins, EpsH, EpsI, EpsJ and EpsK. Pseudopilus is assembled by the polymerization of GspG (also known as PulG) subunits. Pseudopilin proteins have a conserved N-terminal hydrophobic segment followed by a more variable C-terminal periplasmic and globular domain [
].
Growth factor receptor-bound protein 7, SH2 domain
Type:
Domain
Description:
Grb7 (growth factor receptor bound protein 7) is an adapter protein mediating signal transduction from multiple cell surface receptors to diverse downstream pathways [
,
,
]. It contains a Ras-associating (RA) domain, a pleckstrin-homology (PH) domain, a family-specific BPS (between PH and SH2) region and a C-terminal SH2 domain [,
]. This entry represents the C-terminal SH2 domain of Grb7. It is responsible for the binding of this protein to the epidermal growth factor receptor (EGFR, erbB1) via the SH2 domain [
].
Ras GTPase-activating protein 1, N-terminal SH2 domain
Type:
Domain
Description:
Ras GTPase-activating protein 1 (also known as p120-RasGAP) is an inhibitory regulator of the Ras-cyclic AMP pathway [
,
]. Its C-terminal catalytic domain promotes GTP hydrolysis and plays a key role in the regulation of Ras-GTP bound [
]. Its N-terminal part contains two SH2, SH3, PH (pleckstrin homology) and CaLB/C2 (calcium-dependent phospholipid-binding domain) domains, which allow various functions such as anti-/pro-apoptosis, proliferation and cell migration [].Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general the longer isoform contains two SH2 domains, an SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras [
].This entry represents the N-terminal SH2 domain.
Ras GTPase-activating protein 1, C-terminal SH2 domain
Type:
Domain
Description:
Ras GTPase-activating protein 1 (also known as p120-RasGAP) is an inhibitory regulator of the Ras-cyclic AMP pathway [
,
]. Its C-terminal catalytic domain promotes GTP hydrolysis and plays a key role in the regulation of Ras-GTP bound [
]. Its N-terminal part contains two SH2, SH3, PH (pleckstrin homology) and CaLB/C2 (calcium-dependent phospholipid-binding domain) domains, which allow various functions such as anti-/pro-apoptosis, proliferation and cell migration [].Alternative splicing results in two isoforms. The shorter isoform which lacks the N-terminal hydrophobic region, has the same activity, and is expressed in placental tissues. In general the longer isoform contains two SH2 domains, an SH3 domain, a pleckstrin homology (PH) domain, and a calcium-dependent phospholipid-binding C2 domain. The C terminus contains the catalytic domain of RasGap which catalyzes the activation of Ras by hydrolyzing GTP-bound active Ras into an inactive GDP-bound form of Ras [
].This entry represents the C-terminal SH2 domain.
Thiol:disulfide interchange protein DsbD, N-terminal domain superfamily
Type:
Homologous_superfamily
Description:
Folding of secreted proteins within the periplasm of Escherichia coli requires the formation of disulfide bonds, a process that is dependent on the Dsb (disulfide bond) proteins. The reduction of Dsb proteins DsbC, DsbE, and DsbG occurs by transport of electrons from cytoplasmic thioredoxin to the C-terminal thioredoxin-like domain of DsbD (DsbDC). The N-terminal domain of DsbD (DsbDN) is capable of forming disulfides with oxidized DsbC, DsbE, or DsbG as well as with reduced DsbD [
]. This entry represents the DsbDN superfamily. Structurally, this domain has an immunoglobulin-like β-sandwich fold which consists of seven strands arranged in two sheets with a greek-key topology.
