Rxivist logo

Cryo-EM reveals the dynamic interplay between mitochondrial Hsp90 and SdhB folding intermediates

By Yanxin Liu, Daniel Elnatan, Ming Sun, Alexander G. Myasnikov, David A. Agard

Posted 06 Oct 2020
bioRxiv DOI: 10.1101/2020.10.06.327627

TRAP1 is a mitochondrion specific Hsp90, a ubiquitous chaperone family that mediates the folding and maturation of hundreds of 'client' proteins. Through the interaction with client proteins, TRAP1 regulates mitochondrial protein homeostasis, oxidative phosphorylation/glycolysis balance, and plays a critical role in mitochondrial dynamics and disease. However, the molecular mechanism of client protein recognition and remodeling by TRAP1 remains elusive. Here we established the succinate dehydrogenase B subunit (SdhB) from mitochondrial complex II as a client protein for TRAP1 amenable to detailed biochemical and structural investigation. SdhB accelerates the rate of TRAP1 dimer closure and ATP hydrolysis by 5-fold. Cryo-EM structures of the TRAP1:SdhB complex show TRAP1 stabilizes SdhB folding intermediates by trapping an SdhB segment in the TRAP1 lumen. Unexpectedly, client protein binding induces an asymmetric to symmetric transition in the TRAP1 closed state. Our results highlight a client binding mechanism conserved throughout Hsp90s that transcends the need for cochaperones and provide molecular insights into how TRAP1 modulates protein folding within mitochondria. Our structures also suggest a potential role for TRAP1 in Fe-S cluster biogenesis and mitochondrial protein import and will guide small molecule development for therapeutic intervention in specific TRAP1 client interactions. ### Competing Interest Statement The authors have declared no competing interest.

Download data

  • Downloaded 317 times
  • Download rankings, all-time:
    • Site-wide: 68,429 out of 118,665
    • In biophysics: 2,597 out of 4,623
  • Year to date:
    • Site-wide: 24,967 out of 118,665
  • Since beginning of last month:
    • Site-wide: 2,660 out of 118,665

Altmetric data

Downloads over time

Distribution of downloads per paper, site-wide


Sign up for the Rxivist weekly newsletter! (Click here for more details.)