RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation

Apr 18, 2020Cell

RNA Causes G3BP Protein to Change Shape and Cluster, Leading to Stress Granule Formation by Condensation

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Abstract

G3BP undergoes a conformational change to facilitate stress granule assembly when cells are under stress.

Stressed cells release mRNA from polysomes and form stress granules through interactions involving G3BP.
In non-stress conditions, G3BP remains in a compact, auto-inhibited state due to specific molecular interactions.
Upon release from polysomes, unfolded mRNAs disrupt G3BP's auto-inhibitory state, promoting its clustering.
G3BP clusters contribute to the formation of RNA/protein condensates that prevent RNA entanglement.
These condensates can recruit proteins that either aid in stress granule maturation or trigger a transition that may relate to disease.

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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.

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RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation

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