Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones

Prodromou, Chrisostomos, Siligardi, Giuliano, O'Brien, Ronan, Woolfson, Derek N, Regan, Lynne, Panaretou, Barry, Ladbury, John E, Piper, Peter W and Pearl, Laurence H (1999) Regulation of Hsp90 ATPase activity by tetratricopeptide repeat (TPR)-domain co-chaperones. EMBO Journal, 18 (3). pp. 754-762. ISSN 0261-4189

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The in vivo function of the heat shock protein 90 (Hsp90) molecular chaperone is dependent on the binding and hydrolysis of ATP, and on interactions with a variety of co-chaperones containing tetratricopeptide repeat (TPR) domains. We have now analysed the interaction of the yeast TPR-domain co-chaperones Sti1 and Cpr6 with yeast Hsp90 by isothermal titration calorimetry, circular dichroism spectroscopy and analytical ultracentrifugation, and determined the effect of their binding on the inherent ATPase activity of Hsp90. Sti1 and Cpr6 both bind with sub-micromolar affinity, with Sti1 binding accompanied by a large conformational change. Two co-chaperone molecules bind per Hsp90 dimer, and Sti1 itself is found to be a dimer in free solution. The inherent ATPase activity of Hsp90 is completely inhibited by binding of Sti1, but is not affected by Cpr6, although Cpr6 can reactivate the ATPase activity by displacing Sti1 from Hsp90. Bound Sti1 makes direct contact with, and blocks access to the ATP-binding site in the N-terminal domain of Hsp90. These results reveal an important role for TPR-domain co-chaperones as regulators of the ATPase activity of Hsp90, showing that the ATP-dependent step in Hsp90-mediated protein folding occurs after the binding of the folding client protein, and suggesting that ATP hydrolysis triggers client-protein release.

Item Type: Article
Keywords: Adenosine Triphosphatases/chemistry/genetics/*metabolism Binding Sites Carrier Proteins/chemistry/genetics/metabolism *Cyclophilins Fungal Proteins/chemistry/genetics/metabolism HSP90 Heat-Shock Proteins/chemistry/genetics/*metabolism Heat-Shock Proteins Macromolecular Substances Molecular Chaperones/chemistry/genetics/*metabolism Peptidylprolyl Isomerase/chemistry/genetics/metabolism Repetitive Sequences, Amino Acid Saccharomyces cerevisiae/genetics/metabolism Saccharomyces cerevisiae Proteins
Schools and Departments: School of Life Sciences > Biochemistry
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Chrisostomos Prodromou
Date Deposited: 24 Feb 2015 17:54
Last Modified: 24 Feb 2015 17:54
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