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Sequence analysis, function investigation and structure determination have proven to be a powerful methodological combination for studying eukaryotic multidomain proteins. Dozens of protein domain families have been investigated using this approach, leading to significant insights into important cellular signalling mechanisms. The tertiary structure of one such domain, present in signalling proteins from yeast, plants and animals, has recently been determined [1.xNovel modular domain PB1 recognizes PC motif to mediate functional protein– protein interactions. Ito, T. et al. EMBO J. 2001; 20: 3938–3946Crossref | PubMed | Scopus (109)See all References, 2.xStructure and ligand recognition of the PB1 domain: a novel protein module binding to the PC motif. Terasawa, H. et al. EMBO J. 2001; 20: 3947–3956Crossref | PubMed | Scopus (53)See all References]. The PB1 (Phox and Bem1p) domain structure shows that it is a new member of the ubiquitin-like β-grasp fold-containing proteins, members of which also include several RasGTP-binding domain families.The function of PB1 domains has recently been clarified. Ito et al. [1xNovel modular domain PB1 recognizes PC motif to mediate functional protein– protein interactions. Ito, T. et al. EMBO J. 2001; 20: 3938–3946Crossref | PubMed | Scopus (109)See all References[1] found that the Bem1p PB1 domain binds to a region of Cdc24p that contains a sequence motif variously named the octicosapeptide repeat (OPR) [3xNovel domains in NADPH oxidase subunits, sorting nexins, and PtdIns 3-kinases: binding partners of SH3 domains?. Ponting, C.P. Protein Sci. 1996; 5: 2353–2357Crossref | PubMedSee all References[3], the PC (Phox and Cdc) motif [4xThe PC motif: a novel and evolutionarily conserved sequence involved in interaction between p40phox and p67phox, SH3 domain-containing cytosolic factors of the phagocyte NADPH oxidase. Nakamura, R. et al. Eur. J. Biochem. 1998; 251: 583–589Crossref | PubMedSee all References[4] and the AID [atypical protein kinase C (PKC)-interaction domain] motif [5xThe atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. Moscat, J. and Diaz-Meco, M.T. EMBO Reports. 2000; 1: 399–403Crossref | PubMedSee all References[5]. Mutagenesis of the OPR/PC/AID motifs of Cdc24p and p40phox shows that they are necessary for interaction with the PB1 domains of Bem1p and p67phox, respectively [1.xNovel modular domain PB1 recognizes PC motif to mediate functional protein– protein interactions. Ito, T. et al. EMBO J. 2001; 20: 3938–3946Crossref | PubMed | Scopus (109)See all References, 2.xStructure and ligand recognition of the PB1 domain: a novel protein module binding to the PC motif. Terasawa, H. et al. EMBO J. 2001; 20: 3947–3956Crossref | PubMed | Scopus (53)See all References]. This is consistent with findings that deletion of the OPR/PC/AID motifs of MEK5, p62 and Par-6 inhibits binding of the predicted PB1 domain of atypical PKCs (aPKCs) [6xMEK5, a new target of the atypical protein kinase C isoforms in mitogenic signaling. Diaz-Meco, M.T. and Moscat, J. Mol. Cell Biol. 2001; 21: 1218–1227Crossref | PubMed | Scopus (56)See all References[6].Not only do some PB1 domains bind OPR/PC/AID motif-containing regions, but sequence (C.P. Ponting and H. Sumimoto, unpublished; Ref. [1xNovel modular domain PB1 recognizes PC motif to mediate functional protein– protein interactions. Ito, T. et al. EMBO J. 2001; 20: 3938–3946Crossref | PubMed | Scopus (109)See all References[1]) and structural [2xStructure and ligand recognition of the PB1 domain: a novel protein module binding to the PC motif. Terasawa, H. et al. EMBO J. 2001; 20: 3947–3956Crossref | PubMed | Scopus (53)See all References[2] studies show that OPR/PC/AID motifs are all embedded within PB1 domain homologues. Thus, the newly extended PB1 family contains domains (such as those in p40phox, MEK5 and aPKCs) that contain an OPR/PC/AID motif, and others (e.g. those in Bem1p and some plant kinases) that do not.The implication of this observation, given that the Bem1p PB1 domain binds a homologous PB1 domain in Cdc24p, is that some PB1 domains form heterodimers. This process appears to be selective as not all PB1 domains form heterodimers [1xNovel modular domain PB1 recognizes PC motif to mediate functional protein– protein interactions. Ito, T. et al. EMBO J. 2001; 20: 3938–3946Crossref | PubMed | Scopus (109)See all References[1]. Whether these domains possess additional functions remains to be determined. Experimental studies [2xStructure and ligand recognition of the PB1 domain: a novel protein module binding to the PC motif. Terasawa, H. et al. EMBO J. 2001; 20: 3947–3956Crossref | PubMed | Scopus (53)See all References[2] have shown that, although they adopt a β-grasp fold similar to RasGTP-binding domains, Bem1p, p67phox and aPKC PB1 domains lack significant affinity for Ras-like small GTPases.The realization that OPR/PC/AID motifs are localized regions within larger PB1 domains argues that, to avoid ambiguous nomenclature, from now on, these homologous domains should always be referred to as PB1 domains. OPR, PC and AID names should only be used when describing the short localized motif located within PB1 domains. Even then, to avoid confusion, we suggest that a new name ‘OPCA motifs’ (OPR, PC and AID) should replace the previous three names. Under the ‘PB1 domain’ name, a revised multiple alignment of this domain family is now available via the SMART domain database (http://smart.embl-heidelberg.deTest/; Ref. [7xSMART, a simple modular architecture research tool: identification of signaling domains. Schultz, J. et al. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5857–5864Crossref | PubMed | Scopus (2292)See all References[7]).Removal of the nomenclature ambiguity for this family should help to accelerate experimental studies on the 80 or so proteins that contain PB1 domains. Future studies should reveal the molecular roles of these domains, and also whether their functions are comparable with those of their structurally similar ubiquitin-like and Ras-binding domains. |
