Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events
- Argonne National Lab. (ANL), Argonne, IL (United States); Univ. of Chicago, Chicago, IL (United States)
- Stanford Univ., Stanford, CA (United States)
- Univ. of Pennsylvania, Philadelphia, PA (United States)
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Stanford Univ., Stanford, CA (United States); Stanford Univ., Menlo Park, CA (United States). SLAC National Accelerator Lab
Hsp104 is an AAA+ protein disaggregase with powerful amyloid-remodeling activity. All nonmetazoan eukaryotes express Hsp104 while eubacteria express an Hsp104 ortholog, ClpB. However, most studies have focused on Hsp104 from Saccharomyces cerevisiae and ClpB orthologs from two eubacterial species. Thus, the natural spectrum of Hsp104/ClpB molecular architectures and protein-remodeling activities remains largely unexplored. Here, we report two structures of Hsp104 from the thermophilic fungus Calcarisporiella thermophila (CtHsp104), a 2.70Å crystal structure and 4.0Å cryo-electron microscopy structure. Both structures reveal left-handed, helical assemblies with all domains clearly resolved. We thus provide the highest resolution and most complete view of Hsp104 hexamers to date. We also establish that CtHsp104 antagonizes several toxic protein-misfolding events in vivo where S. cerevisiae Hsp104 is ineffective, including rescue of TDP-43, polyglutamine, and α-synuclein toxicity. As a result, we suggest that natural Hsp104 variation is an invaluable, untapped resource for illuminating therapeutic disaggregases for fatal neurodegenerative diseases.
- Research Organization:
- Argonne National Lab. (ANL), Argonne, IL (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)
- Sponsoring Organization:
- Blavatnik Family Foundation; John Hopkins University; Muscular Dystrophy Association; National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID); National Science Foundation (NSF); Target ALS Foundation; USDOE; USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
- Grant/Contract Number:
- AC02-06CH11357; AC02-76SF00515
- OSTI ID:
- 1506849
- Alternate ID(s):
- OSTI ID: 1509898
- Journal Information:
- Structure, Journal Name: Structure Journal Issue: 3 Vol. 27; ISSN 0969-2126
- Publisher:
- ElsevierCopyright Statement
- Country of Publication:
- United States
- Language:
- English
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