RNA-Induced Conformational Switching and Clustering of G3BP Drive Stress Granule Assembly by Condensation.
Carrier Proteins
/ metabolism
Cell Line, Tumor
Cytoplasm
/ metabolism
Cytoplasmic Granules
/ metabolism
DNA Helicases
/ metabolism
HeLa Cells
Humans
Nucleic Acid Conformation
Organelles
/ metabolism
Phosphorylation
Poly-ADP-Ribose Binding Proteins
/ metabolism
RNA Helicases
/ metabolism
RNA Recognition Motif Proteins
/ metabolism
RNA, Messenger
/ metabolism
Ribonucleoproteins
/ metabolism
Stress, Physiological
/ genetics
G3BP
Neurodegenerative disease
RNP granules
liquid-to-solid transition
phase separation
stress granules
stress response
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
16 04 2020
16 04 2020
Historique:
received:
25
01
2019
revised:
23
10
2019
accepted:
20
03
2020
entrez:
18
4
2020
pubmed:
18
4
2020
medline:
24
11
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32302572
pii: S0092-8674(20)30342-1
doi: 10.1016/j.cell.2020.03.049
pmc: PMC7181197
pii:
doi:
Substances chimiques
Carrier Proteins
0
Poly-ADP-Ribose Binding Proteins
0
RNA Recognition Motif Proteins
0
RNA, Messenger
0
Ribonucleoproteins
0
DNA Helicases
EC 3.6.4.-
G3BP1 protein, human
EC 3.6.4.12
RNA Helicases
EC 3.6.4.13
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
346-361.e17Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.
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