6AZY

Crystal structure of Hsp104 R328M/R757M mutant from Calcarisporiella thermophila

6AZY の概要

• エントリーDOI: 10.2210/pdb6azy/pdb
• 分子名称: Heat shock protein Hsp104, ADENOSINE-5'-DIPHOSPHATE (2 entities in total)
• 機能のキーワード: disaggregase, aaa+ atpase, structural genomics, psi-biology, midwest center for structural genomics, mcsg, chaperone
• 由来する生物種: Calcarisporiella thermophila
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 99914.70

構造登録者

Michalska, K.,Bigelow, L.,Hatzos-Skintges, C.,Jedrzejczak, R.,Joachimiak, A.,Midwest Center for Structural Genomics (MCSG) (登録日: 2017-09-13, 公開日: 2018-10-03, 最終更新日: 2023-10-04)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.7 Å)