Allosteric Gating of Son of Sevenless Activity by the Histone Domain

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Feb 6

PMID 20133694

Citations 30

Authors

Kamlesh K Yadav

Dafna Bar-Sagi

Affiliations

Soon will be listed here.

Abstract

Regulated activation of Ras by receptor tyrosine kinases (RTK) constitutes a key transduction step in signaling processes that control an array of fundamental cellular functions including proliferation, differentiation, and survival. The principle mechanism by which Ras is activated down stream of RTKs involves the stimulation of guanine nucleotide exchange by the ubiquitous guanine nucleotide exchange factor Son of sevenless (Sos). In resting conditions, Sos activity is constrained by intramolecular interactions that maintain the protein in an autoinhibited conformation. Structural, biochemical, and genetic studies have implicated the histone domain (Sos-H), which comprises the most N-terminal region of Sos, in the regulation of Sos autoinhibition. However, the molecular underpinnings of this regulatory function are not well understood. In the present study we demonstrate that Sos-H possesses in vitro and in vivo membrane binding activity that is mediated, in part, by the interactions between a cluster of basic residues and phosphatidic acid. This interaction is required for Sos-dependent activation of Ras following EGF stimulation. The inducible association of Sos-H with membranes contributes to the catalytic activity of Sos by forcing the domain to adopt a conformation that destabilizes the autoinhibitory state. Thus, Sos-H plays a critical role in governing the catalytic output of Sos through the coupling of membrane recruitment to the release of autoinhibition.

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