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Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events.

Structure (London, England : 1993) | 2019

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. We suggest that natural Hsp104 variation is an invaluable, untapped resource for illuminating therapeutic disaggregases for fatal neurodegenerative diseases.

Pubmed ID: 30595457 RIS Download

Associated grants

  • Agency: NIGMS NIH HHS, United States
    Id: R24 GM115586
  • Agency: NIGMS NIH HHS, United States
    Id: P41 GM103832
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM079429
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM008076
  • Agency: NIH HHS, United States
    Id: S10 OD021600
  • Agency: NINDS NIH HHS, United States
    Id: F31 NS101807
  • Agency: NIGMS NIH HHS, United States
    Id: U54 GM094585
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM099836
  • Agency: NIAID NIH HHS, United States
    Id: HHSN272201700060C
  • Agency: NIGMS NIH HHS, United States
    Id: K23 GM071399
  • Agency: NIAID NIH HHS, United States
    Id: HHSN272201200026C

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