Structural analysis of autoinhibition in the Ras activator Son of sevenless

Cell. 2004 Oct 29;119(3):393-405. doi: 10.1016/j.cell.2004.10.005.

Abstract

The classical model for the activation of the nucleotide exchange factor Son of sevenless (SOS) involves its recruitment to the membrane, where it engages Ras. The recent discovery that Ras*GTP is an allosteric activator of SOS indicated that the regulation of SOS is more complex than originally envisaged. We now present crystallographic and biochemical analyses of a construct of SOS that contains the Dbl homology-pleckstrin homology (DH-PH) and catalytic domains and show that the DH-PH unit blocks the allosteric binding site for Ras and suppresses the activity of SOS. SOS is dependent on Ras binding to the allosteric site for both a lower level of activity, which is a result of Ras*GDP binding, and maximal activity, which requires Ras*GTP. The action of the DH-PH unit gates a reciprocal interaction between Ras and SOS, in which Ras converts SOS from low to high activity forms as Ras*GDP is converted to Ras*GTP by SOS.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Site
  • Animals
  • Biological Assay
  • COS Cells
  • Chlorocebus aethiops
  • Crystallography, X-Ray
  • Guanosine Diphosphate / metabolism
  • Mutation
  • Protein Structure, Tertiary
  • Son of Sevenless Proteins / chemistry*
  • Son of Sevenless Proteins / genetics
  • Son of Sevenless Proteins / metabolism
  • ras Proteins / metabolism*

Substances

  • Son of Sevenless Proteins
  • Guanosine Diphosphate
  • ras Proteins

Associated data

  • PDB/1XD2
  • PDB/1XD4
  • PDB/1XDV