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

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...

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Detalles Bibliográficos
Autores principales: Guillén-Boixet, Jordina, Kopach, Andrii, Holehouse, Alex S., Wittmann, Sina, Jahnel, Marcus, Schlüßler, 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., Pappu, Rohit V., Alberti, Simon, Franzmann, Titus M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181197/
https://www.ncbi.nlm.nih.gov/pubmed/32302572
http://dx.doi.org/10.1016/j.cell.2020.03.049
Descripción
Sumario: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.