title: Structural analysis of autoinhibition in the Ras activator Son of sevenless.
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.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular and Cell Biology and Department of Chemistry, University of California, Berkeley, CA 94720, USA.
authors.forename: Holger
authors.initials: H
authors.lastname: Sondermann
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Soisson
authors.forename: Sean
authors.initials: S
authors.lastname: Boykevisch
authors.forename: Shao-Song
authors.initials: SS
authors.lastname: Yang
authors.forename: Dafna
authors.initials: D
authors.lastname: Bar-Sagi
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D000495:Allosteric Site; D000818:Animals; D001681:Biological Assay; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D006153:Guanosine Diphosphate / Q000378:metabolism; D009154:Mutation; D017434:Protein Structure, Tertiary; D020664:Son of Sevenless Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D020664:Son of Sevenless Proteins; D006153:Guanosine Diphosphate; D018631:ras Proteins