National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
T32GM071399
United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
F31NS101807
United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
R01GM099836
United States
Department of Energy (DOE, United States)
GM094585
United States
Department of Energy (DOE, United States)
GM115586
United States
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)
P41GM103832
United States
Citation
Journal: Structure / Year: 2019 Title: Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events. Authors: Karolina Michalska / Kaiming Zhang / Zachary M March / Catherine Hatzos-Skintges / Grigore Pintilie / Lance Bigelow / Laura M Castellano / Leann J Miles / Meredith E Jackrel / Edward Chuang ...Authors: Karolina 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 / Abstract: 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 ...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.
History
Deposition
Apr 9, 2018
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Header (metadata) release
Jul 11, 2018
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Map release
Apr 3, 2019
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Update
Mar 13, 2024
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Current status
Mar 13, 2024
Processing site: RCSB / Status: Released
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Structure visualization
Movie
Surface view with section colored by density value
Cryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI TITAN KRIOS
Specialist optics
Energy filter - Name: GIF Quantum LS
Image recording
Film or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Digitization - Frames/image: 3-30 / Number grids imaged: 2 / Number real images: 3786 / Average exposure time: 6.0 sec. / Average electron dose: 31.8 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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