title: Differences in flexibility underlie functional differences in the Ras activators son of sevenless and Ras guanine nucleotide releasing factor 1.
abstract: The Ras-specific nucleotide exchange factor Son of sevenless (Sos) is inactive without Ras bound to a distal allosteric site. In contrast, the catalytic domain of Ras guanine nucleotide releasing factor 1 (RasGRF1) is active intrinsically. By substituting residues from RasGRF1 into Sos, we have generated mutants of Sos with basal activity, partially relieved of their dependence on allosteric activation. We have performed molecular dynamics simulations showing how Ras binding to the allosteric site leads to a bias toward the active conformation of Sos. The trajectories show that Sos fluctuates between active and inactive conformations in the absence of Ras and that the activating mutations favor conformations of Sos that are more permissive to Ras binding at the catalytic site. In contrast, unliganded RasGRF1 fluctuates primarily among active conformations. Our results support the premise that the catalytic domain of Sos has evolved an allosteric activation mechanism that extends beyond the simple process of membrane recruitment.
authors.affiliation: Department of Molecular and Cell Biology, California Institute for Quantitative Biomedical Research, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Tanya S
authors.initials: TS
authors.lastname: Freedman
authors.forename: Holger
authors.initials: H
authors.lastname: Sondermann
authors.forename: Olga
authors.initials: O
authors.lastname: Kuchment
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Friedland
authors.forename: Tanja
authors.initials: T
authors.lastname: Kortemme
authors.forename: John
authors.initials: J
authors.lastname: Kuriyan
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D051379:Mice; D009154:Mutation; D011487:Protein Conformation; D020664:Son of Sevenless Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020666:ras-GRF1 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D020664:Son of Sevenless Proteins; D020666:ras-GRF1