title: The solution structure of the pleckstrin homology domain of human SOS1. A possible structural role for the sequential association of diffuse B cell lymphoma and pleckstrin homology domains.
abstract: A large subset of pleckstrin homology (PH) domains are immediately to the C terminus of diffuse B cell lymphoma (Dbl) homology (DbH) domains. Dbl domains are generally considered to be GTPase-exchange factors; many are proto-oncogenes. PH domains appear to function as membrane-recruitment factors, or have specific protein-protein interactions. Since dual domain (DbH/PH) constructs are known to have significant properties in other pathways, it is possible that a defined interdomain relationship is required for DbH/PH function. We determined the solution structure of the human SOS1 PH domain for a construct partially extended into the preceding DbH domain. There are specific structural contacts between the PH and the vestigial DbH domain. This appears to involve structural elements common to this subfamily of PH domains, and to DbH domains. The human SOS1 PH domain binds to inositol 1,4,5-triphosphate with a approximately 60 mu M affinity. Using chemical shift titration, the binding site is identified to be essentially identical to that observed crystallographically for the inositol 1,4,5-triphosphate complex with the PH domain of phospholipase Cdelta. This site may serve as an interdomain regulator of DbH or other domains' functions. While the overall fold of the human SOS1 PH domain is similar to other PH domains, the size and position of the intrastrand loops and the presence of an N-terminal alpha-helix of the vestigial DbH domain suggest that the subfamily of PH domains associated with DbH domains may be a well defined structural group in which the PH domain is a membrane recruiter and modulator.
authors.affiliation: The Rockefeller University, New York, New York 10021, USA. cowburn@rockefeller.edu
authors.forename: J
authors.initials: J
authors.lastname: Zheng
authors.forename: R H
authors.initials: RH
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Corblan-Garcia
authors.forename: S M
authors.initials: SM
authors.lastname: Cahill
authors.forename: D
authors.initials: D
authors.lastname: Bar-Sagi
authors.forename: D
authors.initials: D
authors.lastname: Cowburn
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry; D005656:Fungal Proteins / Q000648:ultrastructure*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010743:Phospholipids / Q000378:metabolism; D010750:Phosphoproteins; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry; D012097:Repressor Proteins / Q000648:ultrastructure*; D020837:SOS1 Protein; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012996:Solutions
chemical_list: D001798:Blood Proteins; D005656:Fungal Proteins; D020662:Guanine Nucleotide Exchange Factors; C057811:MCF2 protein, human; D010743:Phospholipids; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D020837:SOS1 Protein; D012996:Solutions; C039077:platelet protein P47; D015544:Inositol 1,4,5-Trisphosphate