Poly(A)-binding protein is an ataxin-2 chaperone that regulates biomolecular condensates.
ATXN2
PABPC
amyotrophic lateral sclerosis
microtubule-binding protein
polyQ
protein aggregation
protein phase separation
short linear motif
spinocerebellar ataxia
stress granules
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
15 Jun 2023
15 Jun 2023
Historique:
received:
23
08
2021
revised:
14
03
2023
accepted:
17
05
2023
pmc-release:
15
06
2024
medline:
19
6
2023
pubmed:
10
6
2023
entrez:
9
6
2023
Statut:
ppublish
Résumé
Biomolecular condensation underlies the biogenesis of an expanding array of membraneless assemblies, including stress granules (SGs), which form under a variety of cellular stresses. Advances have been made in understanding the molecular grammar of a few scaffold proteins that make up these phases, but how the partitioning of hundreds of SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, an SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14 aa sequence that acts as a condensation switch and is conserved across the eukaryote lineage. We identify poly(A)-binding proteins as unconventional RNA-dependent chaperones that control this regulatory switch. Our results uncover a hierarchy of cis and trans interactions that fine-tune ataxin-2 condensation and reveal an unexpected molecular function for ancient poly(A)-binding proteins as regulators of biomolecular condensate proteins. These findings may inspire approaches to therapeutically target aberrant phases in disease.
Identifiants
pubmed: 37295429
pii: S1097-2765(23)00381-7
doi: 10.1016/j.molcel.2023.05.025
pmc: PMC10318123
mid: NIHMS1904191
pii:
doi:
Substances chimiques
Ataxin-2
0
Poly(A)-Binding Protein I
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2020-2034.e6Subventions
Organisme : NINDS NIH HHS
ID : P30 NS069375
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI140421
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS097263
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS123743
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests A.D.G. is a scientific founder of Maze Therapeutics. A.S.H. is a scientific consultant for Dewpoint Therapeutics and on the Scientific Advisory Board for Prose Foods.
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