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

Structure. 2019 Mar 5;27(3):449-463.e7. doi: 10.1016/j.str.2018.11.001. Epub 2018 Dec 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphatases / chemistry*
  • Adenosine Triphosphatases / pharmacology*
  • Cryoelectron Microscopy
  • Crystallography, X-Ray
  • DNA-Binding Proteins / antagonists & inhibitors
  • Fungal Proteins / chemistry
  • Fungal Proteins / pharmacology
  • Humans
  • Models, Molecular
  • Mucorales / enzymology*
  • Peptides / antagonists & inhibitors
  • Protein Conformation, alpha-Helical
  • Proteostasis Deficiencies / prevention & control
  • alpha-Synuclein / antagonists & inhibitors


  • DNA-Binding Proteins
  • Fungal Proteins
  • Peptides
  • TARDBP protein, human
  • alpha-Synuclein
  • polyglutamine
  • Adenosine Triphosphatases