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Molecular and Cellular Biology, November 2006, p. 8385-8395, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.02188-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The Middle Domain of Hsp90 Acts as a Discriminator between Different Types of Client Proteins{triangledown}

Patricija Hawle,1,4 Martin Siepmann,1 Anja Harst,1 Marco Siderius,4 H. Peter Reusch,3 and Wolfgang M. J. Obermann1,2*

Protein Folding Group, Institute for Genetics, University of Bonn, Römerstr. 164, D-53117 Bonn, Germany,1 Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 105 11th Street, Research Building 17, Galveston, Texas 77555-0620,2 Department of Clinical Pharmacology, Ruhr University, Universitätsstr. 150, D-44801 Bochum, Germany,3 Department of Biochemistry and Molecular Biology, Faculty of Science, Vrije Universiteit, 1081 HV Amsterdam, The Netherlands4

Received 11 November 2005/ Returned for modification 27 December 2005/ Accepted 28 August 2006

The mechanism of client protein activation by Hsp90 is enigmatic, and it is uncertain whether Hsp90 employs a common route for all proteins. Using a mutational analysis approach, we investigated the activation of two types of client proteins, glucocorticoid receptor (GR) and the kinase v-Src by the middle domain of Hsp90 (Hsp90M) in vivo. Remarkably, the overall cellular activity of v-Src was highly elevated in a W300A mutant yeast strain due to a 10-fold increase in cellular protein levels of the kinase. In contrast, the cellular activity of GR remained almost unaffected by the W300A mutation but was dramatically sensitive to S485Y and T525I exchanges. In addition, we show that mutations S485Y and T525I in Hsp90M reduce the ATP hydrolysis rate, suggesting that Hsp90 ATPase is more tightly regulated than assumed previously. Therefore, the activation of GR and v-Src has various demands on Hsp90 biochemistry and is dependent on separate functional regions of Hsp90M. Thus, Hsp90M seems to discriminate between different substrate types and to adjust the molecular chaperone for proper substrate activation.

* Corresponding author. Mailing address: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, 105 11th Street, Research Building 17, Galveston, TX 77555-0620. Phone: (409) 747-1214. Fax: (409) 747-2200. E-mail: wmoberma{at}utmb.edu.

{triangledown} Published ahead of print on 18 September 2006.

Molecular and Cellular Biology, November 2006, p. 8385-8395, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.02188-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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