HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain
- Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- University of Konstanz, Germany
- Max Planck Institute for the Physics of Complex Systems, Germany
- Biotec, TU Dresden, Germany
- University of Modena and Reggio Emilia, Italy
Abstract
Aberrant liquid-to-solid phase transitions of biomolecular condensates have been linked to various neurodegenerative diseases. However, the underlying molecular interactions that drive aging remain enigmatic. Here, we develop quantitative time-resolved crosslinking mass spectrometry to monitor protein interactions and dynamics inside condensates formed by the protein fused in sarcoma (FUS). We identify misfolding of the RNA recognition motif (RRM) of FUS as a key driver of condensate ageing. We demonstrate that the small heat shock protein HspB8 partitions into FUS condensates via its intrinsically disordered domain and prevents condensate hardening via condensate-specific interactions that are mediated by its α-crystallin domain (αCD). These αCD-mediated interactions are altered in a disease-associated mutant of HspB8, which abrogates the ability of HspB8 to prevent condensate hardening. We propose that stabilizing aggregation-prone folded RNA-binding domains inside condensates by molecular chaperones may be a general mechanism to prevent aberrant phase transitions.
Data availability
All data generated or analysed during this study are included in this published article (and its supplementary information files). The MS data (raw files, xQuest, xTract and in-house quantitation output files) have been deposited to the ProteomeXchange Consortium via the PRIDE (60) partner repository with the dataset identifier PXD021114 (Username: reviewer33076@ebi.ac.uk; Password: 5atfkbP8) and PXD021115 (Username: reviewer54149@ebi.ac.uk; Password: UZW7Gnr5).
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Funding
Deutsche Forschungsgemeinschaft (STE 2517/1-1)
- Florian Stengel
Konstanz Research School Chemical Biology (Chemicals and small Equipment Purchase)
- Florian Stengel
Deutsche Forschungsgemeinschaft (Cluster of Excellence Physics of Life"")
- Dr. Simon Alberti
Deutsche Forschungsgemeinschaft (Cluster of Excellence Physics of Life"")
- Anthony A Hyman
EU Joint Programme – Neurodegenerative Disease Research (Neurodegenerative Disease Research (JPND))
- Serena Carra
EU Joint Programme – Neurodegenerative Disease Research (Neurodegenerative Disease Research (JPND))
- Dr. Simon Alberti
AriSLA Foundation (Granulopathy and MLOpathy)
- Serena Carra
MAECI (Dissolve_ALS)
- Serena Carra
MIUR (E91I18001480001)
- Serena Carra
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2021, Boczek et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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