Poly(A)-binding protein is an ataxin-2 chaperone that emulsifies biomolecular condensates

  • 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 that dictates the behavior of a few key scaffold proteins that make up these phases but how the partitioning of hundreds of other SG proteins is regulated remains largely unresolved. While investigating the rules that govern the condensation of ataxin-2, a SG protein implicated in neurodegenerative disease, we unexpectedly identified a short 14aa sequence that acts as an ataxin-2 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 a new molecular function for ancient poly(A)-binding proteins as emulsifiers of biomolecular condensate proteins. These findings may inspire novel approaches to therapeutically target aberrant phases in disease.

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Author:Steven BoeynaemsORCiD, Yanniv DoroneORCiD, Anca Marian, Victoria ShabardinaORCiDGND, Guozhong Huang, Garam Kim, Anushka Sanyal, Nesli Ece ŞenGND, Roberto DocampoORCiD, Iñaki Ruiz-TrilloORCiDGND, Keren LaskerORCiD, Georg AuburgerORCiDGND, Edor KabashiORCiD, Aaron D. GitlerORCiD
Parent Title (English):bioRxiv
Document Type:Preprint
Date of Publication (online):2021/08/23
Date of first Publication:2021/08/23
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2023/07/18
Tag:amyotrophic lateral sclerosis; frontotemporal dementia; phase separation; polyQ; prion-like; protein aggregation; short linear motif; spinocerebellar ataxia; stress granules
Page Number:34
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International