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A molecular assembly phase transition and kinetic proofreading modulate Ras activation by SOS
William Y C Huang1, Steven Alvarez2, Yasushi Kondo1,3,4
1Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Science (New York, N.Y.)
|March 9, 2019
Summary
The Son of Sevenless (SOS) protein, a Ras activator, shows a delay in activation after membrane binding. This delay acts as kinetic proofreading, regulated by a LAT-Grb2-SOS phase transition.
Area of Science:
- Molecular and Cellular Biology
- Signal Transduction
- Biophysics
Background:
- The guanine nucleotide exchange factor (GEF) Son of Sevenless (SOS) is a crucial activator of Ras signaling.
- SOS is autoinhibited in the cytosol and requires membrane recruitment for activation, a process involving structural rearrangements.
- This membrane-induced structural change introduces a temporal delay between SOS recruitment and its catalytic activity.
Purpose of the Study:
- To precisely measure the time delay between initial membrane recruitment and the onset of GEF activity for individual SOS molecules.
- To investigate the role of this temporal delay in the receptor-mediated activation of Ras.
- To explore how the LAT-Grb2-SOS complex formation influences SOS activation kinetics at the membrane.
Main Methods:
- Development of a single-molecule assay utilizing microarrays of Ras-functionalized supported membranes.
- Real-time observation of individual SOS molecules to resolve the time from membrane recruitment to the initiation of GEF activity.
- Analysis of the SOS activation time distribution to characterize the kinetics of autoinhibition release.
Main Results:
- The activation time distribution of SOS exhibited a characteristic rise-and-fall shape.
- A significant mean timescale of approximately 50 seconds was observed for SOS activation after membrane recruitment.
- This kinetic behavior supports the concept of kinetic proofreading in Ras activation.
- The LAT-Grb2-SOS phosphotyrosine-driven phase transition was identified as a modulator of this kinetic proofreading mechanism.
Conclusions:
- The observed delay in SOS activation serves as a kinetic proofreading mechanism, ensuring fidelity in Ras signaling.
- This mechanism is finely tuned by the formation of a LAT-Grb2-SOS phase-separated condensate at the plasma membrane.
- Understanding these dynamics provides insights into the regulation of Ras-mediated cellular processes.
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