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 paper / PDB coordinates
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- 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.
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