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

Jie Zheng, R. H. Chen, S. Corblan-Garcia, Sean M. Cahill, Dafna Bar-Sagi, David Cowburn

Research output: Contribution to journalArticle

56 Scopus citations

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 ~60 μM 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 Cδ. 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 a-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.

Original languageEnglish (US)
Pages (from-to)30340-30344
Number of pages5
JournalJournal of Biological Chemistry
Volume272
Issue number48
DOIs
StatePublished - Nov 28 1997
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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