HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain
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 prote...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/69377 |
| _version_ | 1811200982089990144 |
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| author | Edgar E Boczek Julius Fürsch Marie Laura Niedermeier Louise Jawerth Marcus Jahnel Martine Ruer-Gruß Kai-Michael Kammer Peter Heid Laura Mediani Jie Wang Xiao Yan Andrej Pozniakovski Ina Poser Daniel Mateju Lars Hubatsch Serena Carra Simon Alberti Anthony A Hyman Florian Stengel |
| author_facet | Edgar E Boczek Julius Fürsch Marie Laura Niedermeier Louise Jawerth Marcus Jahnel Martine Ruer-Gruß Kai-Michael Kammer Peter Heid Laura Mediani Jie Wang Xiao Yan Andrej Pozniakovski Ina Poser Daniel Mateju Lars Hubatsch Serena Carra Simon Alberti Anthony A Hyman Florian Stengel |
| author_sort | Edgar E Boczek |
| collection | DOAJ |
| description | 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 of FUS as a key driver of condensate aging. 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. |
| first_indexed | 2024-04-12T02:13:28Z |
| format | Article |
| id | doaj.art-85bf8344d0894177804ff718a7d76096 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:13:28Z |
| publishDate | 2021-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-85bf8344d0894177804ff718a7d760962022-12-22T03:52:19ZengeLife Sciences Publications LtdeLife2050-084X2021-09-011010.7554/eLife.69377HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domainEdgar E Boczek0Julius Fürsch1Marie Laura Niedermeier2Louise Jawerth3Marcus Jahnel4Martine Ruer-Gruß5Kai-Michael Kammer6Peter Heid7Laura Mediani8Jie Wang9Xiao Yan10Andrej Pozniakovski11Ina Poser12Daniel Mateju13Lars Hubatsch14https://orcid.org/0000-0003-1934-7437Serena Carra15Simon Alberti16Anthony A Hyman17Florian Stengel18https://orcid.org/0000-0003-1447-4509Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Dewpoint Therapeutics GmbH, Dresden, GermanyUniversity of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, GermanyUniversity of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyUniversity of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, GermanyUniversity of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, GermanyDepartment of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, ItalyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Dewpoint Therapeutics GmbH, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Max Planck Institute for the Physics of Complex Systems, Dresden, GermanyDepartment of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, ItalyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Biotechnology Center, Technische Universität Dresden, Dresden, GermanyMax Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany; Center for Systems Biology Dresden (CSBD), Dresden, GermanyUniversity of Konstanz, Department of Biology, Konstanz, Germany; Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, GermanyAberrant 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 of FUS as a key driver of condensate aging. 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.https://elifesciences.org/articles/69377molecular condensatesRRMchaperonestime-resolved quantitative XL-MSFUSaging |
| spellingShingle | Edgar E Boczek Julius Fürsch Marie Laura Niedermeier Louise Jawerth Marcus Jahnel Martine Ruer-Gruß Kai-Michael Kammer Peter Heid Laura Mediani Jie Wang Xiao Yan Andrej Pozniakovski Ina Poser Daniel Mateju Lars Hubatsch Serena Carra Simon Alberti Anthony A Hyman Florian Stengel HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain eLife molecular condensates RRM chaperones time-resolved quantitative XL-MS FUS aging |
| title | HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain |
| title_full | HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain |
| title_fullStr | HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain |
| title_full_unstemmed | HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain |
| title_short | HspB8 prevents aberrant phase transitions of FUS by chaperoning its folded RNA-binding domain |
| title_sort | hspb8 prevents aberrant phase transitions of fus by chaperoning its folded rna binding domain |
| topic | molecular condensates RRM chaperones time-resolved quantitative XL-MS FUS aging |
| url | https://elifesciences.org/articles/69377 |
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