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"metadata": {
"accession": "PS50010",
"entry_id": null,
"type": "domain",
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"source_database": "profile",
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"integrated": "IPR000219",
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"name": {
"name": "Dbl homology (DH) domain profile",
"short": "DH_2"
},
"description": [
{
"text": "<p>The Rho family GTPases Rho, Rac and CDC42 regulate a diverse array of cellular\nprocesses. Like all members of the Ras superfamily, the Rho proteins cycle\nbetween active GTP-bound and inactive GDP-bound conformational states.\nActivation of Rho proteins, through release of bound GDP and subsequent\nbinding of GTP, is catalyzed by guanine nucleotide exchange factors (GEFs) in\nthe Dbl family. The proteins encoded by members of the Dbl family share a\ncommon domain of about 200 residues (designated the Dbl homology or DH domain)\nthat has been shown to encode a GEF activity specific for a number of Rho\nfamily members. In addition, all family members possess a second, shared\ndomain designated the pleckstrin homology (PH) domain. Trio\nand its homolog UNC-73 are unique within the Dbl family insomuch as they\nencode two distinct DH/PH domain modules. The PH domain is invariably located\nimmediately C-terminal to the DH domain and this invariant topography suggests\na functional interdependence between these two structural modules. Biochemical\ndata have established the role of the conserved DH domain in Rho GTPase\ninteraction and activation, and the role of the tandem PH domain in\nintracellular targeting and/or regulation of DH domain function. The DH domain\nof Dbl has been shown to mediate oligomerization that is mostly homophilic in\nnature. In addition to the tandem DH/PH domains Dbl family GEFs contain\ndiverse structural motifs like serine/threonine kinase, RBD,\nPDZ, RGS, IQ, REM, Cdc25\nRasGEF, CH, SH2, SH3, EF, spectrin or Ig [[cite:PUB00017987]][[cite:PUB00017988]][[cite:PUB00017989]][[cite:PUB00017990]].\n\nThe DH domain is composed of three structurally conserved regions separated by\nmore variable regions. It does not share significant sequence homology with\nother subtypes of small G-protein GEF motifs such as the Cdc25 domain and the\nSec7 domain, which specifically interact with Ras and ARF\nfamily small GTPases, respectively, nor with other Rho protein interactive\nmotifs, indicating that the Dbl family proteins are evolutionarily unique. The\nDH domain is composed of 11 alpha helices that are folded into a flattened,\nelongated alpha-helix bundle in which two of the three conserved regions,\nconserved region 1 (CR1) and conserved region 3 (CR3), are exposed near the\ncenter of one surface. CR1 and CR3, together with a part of alpha-6 and the\nDH/PH junction site, constitute the Rho GTPase interacting pocket [[cite:PUB00017988]][[cite:PUB00017989]][[cite:PUB00017991]].\n\nSome proteins known to contain a DH domain are listed below:\n\n - Dbl (or mcf-2) oncogene from mammals. Dbl is a GEF for a ras-like protein\n known as G25K or CDC42Hs.\n - CDC24 from yeast. CDC24 is a GEF that acts on the ras-like protein CDC42 to\n regulate bud site assembly and mating pheromone signaling.\n - scd1 from fission yeast. It is a cell cycle regulatory protein with global\n homology to CDC24.\n - p140-RAS GEF (cdc25Mm) from mammals. This protein, a GEF for ras, possesses\n both a domain belonging to the CDC24 family and one belonging to the CDC25\n family.\n - Break cluster region (Bcr) oncogene from mammals. Bcr can form a chimera\n with the abl protein and then cause chronic myelogenous leukemia (CML). Bcr\n acts on p21-rac proteins.\n - Abr, a protein that shares strong sequence organization and identity with\n Bcr, but lacks the serine/threonine kinase domain that is found at the N-\n terminus of Bcr.\n - T-lymphoma invasion and metastasis inducing protein 1 (Tiam1 protein). Acts\n as a GEF for rac1, CDC42, and to a lesser extent rhoA.\n - Oncogenes vav and vav2 from mammals. The target of these proteins are not\n yet known.\n - Oncogene ect2 from mouse. The target of this protein is not yet known.\n\nThe profile we developed covers the entire DH domain.</p>",
"llm": false,
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}
],
"wikipedia": null,
"literature": {
"PUB00017987": {
"PMID": 8276860,
"ISBN": null,
"volume": "269",
"issue": "1",
"year": 1994,
"title": "Cellular transformation and guanine nucleotide exchange activity are catalyzed by a common domain on the dbl oncogene product.",
"URL": null,
"raw_pages": "62-5",
"medline_journal": "J Biol Chem",
"ISO_journal": "J. Biol. Chem.",
"authors": [
"Hart MJ",
"Eva A",
"Zangrilli D",
"Aaronson SA",
"Evans T",
"Cerione RA",
"Zheng Y."
],
"DOI_URL": "http://intl.jbc.org/cgi/reprint/269/1/62.pdf"
},
"PUB00017991": {
"PMID": 9846881,
"ISBN": null,
"volume": "5",
"issue": "12",
"year": 1998,
"title": "Structure and mutagenesis of the Dbl homology domain.",
"URL": null,
"raw_pages": "1098-107",
"medline_journal": "Nat Struct Biol",
"ISO_journal": "Nat. Struct. Biol.",
"authors": [
"Aghazadeh B",
"Zhu K",
"Kubiseski TJ",
"Liu GA",
"Pawson T",
"Zheng Y",
"Rosen MK."
],
"DOI_URL": "http://dx.doi.org/10.1038/4209"
},
"PUB00017988": {
"PMID": 9061011,
"ISBN": null,
"volume": "1332",
"issue": "1",
"year": 1997,
"title": "Dbl family proteins.",
"URL": null,
"raw_pages": "F1-23",
"medline_journal": "Biochim Biophys Acta",
"ISO_journal": "Biochim. Biophys. Acta",
"authors": [
"Whitehead IP",
"Campbell S",
"Rossman KL",
"Der CJ."
],
"DOI_URL": "http://dx.doi.org/10.1016/S0304-419X(96)00040-6"
},
"PUB00017989": {
"PMID": 11738596,
"ISBN": null,
"volume": "26",
"issue": "12",
"year": 2001,
"title": "Dbl family guanine nucleotide exchange factors.",
"URL": null,
"raw_pages": "724-32",
"medline_journal": "Trends Biochem Sci",
"ISO_journal": "Trends Biochem. Sci.",
"authors": [
"Zheng Y."
],
"DOI_URL": "http://dx.doi.org/10.1016/S0968-0004(01)01973-9"
},
"PUB00017990": {
"PMID": 11134331,
"ISBN": null,
"volume": "21",
"issue": "2",
"year": 2001,
"title": "Oligomerization of DH domain is essential for Dbl-induced transformation.",
"URL": null,
"raw_pages": "425-37",
"medline_journal": "Mol Cell Biol",
"ISO_journal": "Mol. Cell. Biol.",
"authors": [
"Zhu K",
"Debreceni B",
"Bi F",
"Zheng Y."
],
"DOI_URL": "http://dx.doi.org/10.1128/MCB.21.2.425-437.2001"
}
},
"set_info": null,
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"subfamilies": 0,
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"matches": 154946,
"pathways": 0,
"proteins": 150164,
"proteomes": 2941,
"sets": 0,
"structural_models": {
"alphafold": 91794,
"bfvd": 1
},
"structures": 144,
"taxa": 8423
},
"entry_annotations": {},
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"is_llm": false,
"is_reviewed_llm": false,
"is_updated_llm": false,
"representative_structure": {
"accession": "9jb3",
"name": "Crystal structure of DH domain of human FGD6"
}
}
}
