Asymmetric apical domain states of mitochondrial Hsp60 coordinate substrate engagement and chaperonin assembly.

Autor: Braxton JR; Graduate Program in Chemistry and Chemical Biology, University of California San Francisco, San Francisco, CA, USA.; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA.; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA., Shao H; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA., Tse E; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA., Gestwicki JE; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA. jason.gestwicki@ucsf.edu., Southworth DR; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA. daniel.southworth@ucsf.edu.
Jazyk: angličtina
Zdroj: Nature structural & molecular biology [Nat Struct Mol Biol] 2024 Dec; Vol. 31 (12), pp. 1848-1858. Date of Electronic Publication: 2024 Jul 01.
DOI: 10.1038/s41594-024-01352-0
Abstrakt: The mitochondrial chaperonin, mitochondrial heat shock protein 60 (mtHsp60), promotes the folding of newly imported and transiently misfolded proteins in the mitochondrial matrix, assisted by its co-chaperone mtHsp10. Despite its essential role in mitochondrial proteostasis, structural insights into how this chaperonin progresses through its ATP-dependent client folding cycle are not clear. Here, we determined cryo-EM structures of a hyperstable disease-associated human mtHsp60 mutant, V72I. Client density is identified in three distinct states, revealing interactions with the mtHsp60 apical domains and C termini that coordinate client positioning in the folding chamber. We further identify an asymmetric arrangement of the apical domains in the ATP state, in which an alternating up/down configuration positions interaction surfaces for simultaneous recruitment of mtHsp10 and client retention. Client is then fully encapsulated in mtHsp60-10, revealing prominent contacts at two discrete sites that potentially support maturation. These results identify distinct roles for the apical domains in coordinating client capture and progression through the chaperone cycle, supporting a conserved mechanism of group I chaperonin function.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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