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

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Science  08 Mar 2019:
Vol. 363, Issue 6431, pp. 1098-1103
DOI: 10.1126/science.aau5721

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Organized for action

It is becoming increasingly clear that biomolecular condensates, which are concentrations of macromolecules not surrounded by a membrane, are a key organizational structure in eukaryotic cells (see the Perspective by Martin and Mittag). Now, two papers show how such condensates function in actin assembly or in a Ras signaling pathway. In both cases, the condensates form at the plasma membrane and increase the activity of signaling proteins by increasing their membrane dwell times. Case et al. show that the dwell time is dependent on cluster stoichiometry, so that stoichiometry of regulatory proteins can control actin assembly. Huang et al. demonstrate that the longer dwell time allows kinetic proofreading in receptor-mediated activation of Ras.

Science, this issue p. 1093, p. 1098; see also p. 1036

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.

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