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

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 neur...

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Bibliographic Details
Published in:	Biophysical journal Vol. 122; no. 17; pp. 3458 - 3468
Main Authors:	Mondol, Tanumoy, Silbermann, Laura-Marie, Schimpf, Julia, Vollmar, Leonie, Hermann, Bianca, Tych, Katarzyna (Kasia), Hugel, Thorsten
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-09-2023 The Biophysical Society
Subjects:	Adenosine Triphosphatases - metabolism HSP90 Heat-Shock Proteins - metabolism Humans Molecular Chaperones - metabolism Molecular Conformation
Online Access:	Get full text
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0006-3495 1542-0086 1542-0086
DOI:	10.1016/j.bpj.2023.07.020