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

  • Guillen-Boixet, Jordina
  • Kopach, Andrii
  • Holehouse, Alex S.
  • Wittmann, Sina
  • Jahnel, Marcus
  • Schluessler, Raimund
  • Kim, Kyoohyun
  • Trussina, Irmela R. E. A.
  • Wang, Jie
  • Mateju, Daniel
  • Poser, Ina
  • Maharana, Shovamayee
  • Ruer-Gruss, Martine
  • Richter, Doris
  • Zhang, Xiaojie
  • Chang, Young-Tae
  • Guck, Jochen
  • Honigmann, Alf
  • Mahamid, Julia
  • Hyman, Anthony A.
  • And 3 more
Publication Date
Apr 01, 2020
[email protected]
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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, G3BPadopts 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 hetero-typic multivalent interactions may be a general principle underlying RNP granule assembly. / 1 / N

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