Structural Analysis of Autoinhibition in the Ras Activator Son of Sevenless
Holger Sondermann*, Stephen M. Soisson*, Sean Boykevisch, Shao-Song Yang,
Dafna Bar-Sagi, and John Kuriyan
Cell. 2004 Oct 29;119(3):393-405.
Link to Cell Press
*These authors contributed equally to this work.
Abstract / Figures from the
/ PDB coordinates
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- and 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.
Illustrations from the paper. Click on the
small image to get a bigger one.
PDB code 1XD2
PDB code 1XD4
PDB code 1XDV