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A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS.


ABSTRACT: The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) is a key Ras activator that is autoinhibited in the cytosol and activates upon membrane recruitment. Autoinhibition release involves structural rearrangements of the protein at the membrane and thus introduces a delay between initial recruitment and activation. In this study, we designed a single-molecule assay to resolve the time between initial receptor-mediated membrane recruitment and the initiation of GEF activity of individual SOS molecules on microarrays of Ras-functionalized supported membranes. The rise-and-fall shape of the measured SOS activation time distribution and the long mean time scale to activation (~50 seconds) establish a basis for kinetic proofreading in the receptor-mediated activation of Ras. We further demonstrate that this kinetic proofreading is modulated by the LAT (linker for activation of T cells)-Grb2-SOS phosphotyrosine-driven phase transition at the membrane.

SUBMITTER: Huang WYC 

PROVIDER: S-EPMC6563836 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS.

Huang William Y C WYC   Alvarez Steven S   Kondo Yasushi Y   Lee Young Kwang YK   Chung Jean K JK   Lam Hiu Yue Monatrice HYM   Biswas Kabir H KH   Kuriyan John J   Groves Jay T JT  

Science (New York, N.Y.) 20190307 6431


The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) is a key Ras activator that is autoinhibited in the cytosol and activates upon membrane recruitment. Autoinhibition release involves structural rearrangements of the protein at the membrane and thus introduces a delay between initial recruitment and activation. In this study, we designed a single-molecule assay to resolve the time between initial receptor-mediated membrane recruitment and the initiation of GEF activity of indivi  ...[more]

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