Cell
Volume 181, Issue 2, 16 April 2020, Pages 346-361.e17
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Article
RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation

https://doi.org/10.1016/j.cell.2020.03.049Get rights and content
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Highlights

  • Under non-stressed conditions, G3BP adopts a compact auto-inhibited state

  • Conformational expansion of G3BP increases the interaction valences

  • G3BP clusters crosslink RNA to assemble stress granules upon cellular stress

  • G3BP condensates prevent RNA entanglement

Summary

Stressed cells shut down translation, release mRNA molecules from polysomes, and form stress granules (SGs) via a network of interactions that involve G3BP. Here we focus on the mechanistic underpinnings of SG assembly. We show that, under non-stress conditions, G3BP adopts a compact auto-inhibited state stabilized by electrostatic intramolecular interactions between the intrinsically disordered acidic tracts and the positively charged arginine-rich region. Upon release from polysomes, unfolded mRNAs outcompete G3BP auto-inhibitory interactions, engendering a conformational transition that facilitates clustering of G3BP through protein-RNA interactions. Subsequent physical crosslinking of G3BP clusters drives RNA molecules into networked RNA/protein condensates. We show that G3BP condensates impede RNA entanglement and recruit additional client proteins that promote SG maturation or induce a liquid-to-solid transition that may underlie disease. We propose that condensation coupled to conformational rearrangements and heterotypic multivalent interactions may be a general principle underlying RNP granule assembly.

Keywords

stress granules
RNP granules
G3BP
phase separation
liquid-to-solid transition
Neurodegenerative disease
stress response

Cited by (0)

8

These authors contributed equally

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Present address: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland

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Lead Contact