6D00

Calcarisporiella thermophila Hsp104

Summary for 6D00

• Entry DOI: 10.2210/pdb6d00/pdb
• Related: 6AZY
• EMDB information: 7782
• Descriptor: Calcarisporiella thermophila Hsp104, ADENOSINE-5'-DIPHOSPHATE (2 entities in total)
• Functional Keywords: spiral hexamer; antagonize toxin; adp-binding state, chaperone
• Biological source: Calcarisporiella thermophila
• Total number of polymer chains: 6
• Total formula weight: 598593.07

Authors

Zhang, K.,Pintilie, G. (deposition date: 2018-04-09, release date: 2019-04-03, Last modification date: 2024-03-13)

Primary citation

Michalska, K.,Zhang, K.,March, Z.M.,Hatzos-Skintges, C.,Pintilie, G.,Bigelow, L.,Castellano, L.M.,Miles, L.J.,Jackrel, M.E.,Chuang, E.,Jedrzejczak, R.,Shorter, J.,Chiu, W.,Joachimiak, A.
Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events.
Structure, 27:449-463.e7, 2019

PubMed 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 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: 30595457
DOI: 10.1016/j.str.2018.11.001

Experimental method

ELECTRON MICROSCOPY (4 Å)