CellApr 18, 2020

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

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

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.

Simplified

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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Competing interests

Declaration of Interests S.A. and R.V.P. are advisors on the scientific advisory board of Dewpoint Therapeutics. A.A.H. is a co-founder of Dewpoint Therapeutics.

PubMed

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

Abstract

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Abstract

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