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TitleStructure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events.
Journal, issue, pagesStructure, Vol. 27, Issue 3, Page 449-463.e7, Year 2019
Publish dateMar 5, 2019
AuthorsKarolina Michalska / Kaiming Zhang / Zachary M March / Catherine Hatzos-Skintges / Grigore Pintilie / Lance Bigelow / Laura M Castellano / Leann J Miles / Meredith E Jackrel / Edward Chuang / Robert Jedrzejczak / James Shorter / Wah Chiu / Andrzej Joachimiak /
PubMed AbstractHsp104 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 ...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.
External linksStructure / PubMed:30595457 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 4.0 Å
Structure data

EMDB-7782, PDB-6d00:
Calcarisporiella thermophila Hsp104
Method: EM (single particle) / Resolution: 4.0 Å

PDB-6azy:
Crystal structure of Hsp104 R328M/R757M mutant from Calcarisporiella thermophila
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

Source
  • calcarisporiella thermophila (fungus)
KeywordsCHAPERONE / disaggregase / AAA+ ATPase / Structural Genomics / PSI-Biology / Midwest Center for Structural Genomics / MCSG / Spiral hexamer; antagonize toxin; ADP-binding state

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