Aha1 regulates Hsp90's conformation and function in a stoichiometry-dependent way

Tanumoy Mondol, Laura-Marie Silbermann, Julia Schimpf, Leonie Vollmar, Bianca Hermann, Katarzyna Kasia Tych*, Thorsten Hugel*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
73 Downloads (Pure)

Abstract

The heat shock protein 90 (Hsp90) is a molecular chaperone, which plays a key role in eukaryotic protein homeostasis. Co-chaperones assist Hsp90 in client maturation and in regulating essential cellular processes such as cell survival, signal transduction, gene regulation, hormone signaling and neurodegeneration. Aha1 (activator of Hsp90 ATPase) is a unique co-chaperone known to stimulate the ATP hydrolysis of Hsp90, but the mechanism of their interaction is still unclear. In this report, we show that one or two Aha1 can bind to one Hsp90 dimer and that the binding stoichiometry affects Hsp90's conformation, kinetics, ATPase activity and stability. In particular, a coordination of two Aha1 molecules can be seen in stimulating the ATPase activity of Hsp90 and the unfolding of the middle domain, while the conformational equilibrium and kinetics are hardly affected by the stoichiometry of bound Aha1. Altogether, we show a regulation mechanism through the stoichiometry of Aha1 going far beyond a regulation of Hsp90's conformation.

Original languageEnglish
Pages (from-to) 3458-3468
Number of pages22
JournalBiophysical Journal
Volume122
Issue number17
Early online date27-Jul-2023
DOIs
Publication statusPublished - 5-Sept-2023

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