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.


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*


  • Son of Sevenless Proteins
  • Guanosine Diphosphate
  • ras Proteins

Associated data

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