Stoichiometry controls activity of phase-separated clusters of actin signaling proteins

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Science  08 Mar 2019:
Vol. 363, Issue 6431, pp. 1093-1097
DOI: 10.1126/science.aau6313

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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


Biomolecular condensates concentrate macromolecules into foci without a surrounding membrane. Many condensates appear to form through multivalent interactions that drive liquid-liquid phase separation (LLPS). LLPS increases the specific activity of actin regulatory proteins toward actin assembly by the Arp2/3 complex. We show that this increase occurs because LLPS of the Nephrin–Nck–N-WASP signaling pathway on lipid bilayers increases membrane dwell time of N-WASP and Arp2/3 complex, consequently increasing actin assembly. Dwell time varies with relative stoichiometry of the signaling proteins in the phase-separated clusters, rendering N-WASP and Arp2/3 activity stoichiometry dependent. This mechanism of controlling protein activity is enabled by the stoichiometrically undefined nature of biomolecular condensates. Such regulation should be a general feature of signaling systems that assemble through multivalent interactions and drive nonequilibrium outputs.

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