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Journal Article

HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain.

MPS-Authors
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Boczek,  Edgar
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons189545

Jawerth,  Louise
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons204000

Jahnel,  Marcus
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219595

Ruer-Gruß,  Martine
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons222397

Wang,  Jie
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219545

Poser,  Ina
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219433

Mateju,  Daniel
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons184590

Hubatsch,  Lars
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

/persons/resource/persons219253

Hyman,  Anthony
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Boczek, E., Fürsch, J., Niedermeier, M. L., Jawerth, L., Jahnel, M., Ruer-Gruß, M., et al. (2021). HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA binding domain. eLife, 10: e69377. doi:10.7554/eLife.69377.


Cite as: https://hdl.handle.net/21.11116/0000-000A-0B93-4
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.