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Conformational dynamics of the molecular chaperone Hsp90

Published online by Cambridge University Press:  18 March 2011

Kristin A. Krukenberg ,
Timothy O. Street ,
Laura A. Lavery  and
David A. Agard
Kristin A. Krukenberg
Affiliation:
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
Timothy O. Street
Affiliation:
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
Laura A. Lavery
Affiliation:
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA
David A. Agard*
Affiliation:
Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA The Howard Hughes Medical Institute, University of California, San Francisco, CA, USA
*
*Author for correspondence: D. A. Agard, Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA. Tel.: 415-476-2521; Fax: 41-476-1902; Email: agard@msg.ucsf.edu
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Abstract

The ubiquitous molecular chaperone Hsp90 makes up 1–2% of cytosolic proteins and is required for viability in eukaryotes. Hsp90 affects the folding and activation of a wide variety of substrate proteins including many involved in signaling and regulatory processes. Some of these substrates are implicated in cancer and other diseases, making Hsp90 an attractive drug target. Structural analyses have shown that Hsp90 is a highly dynamic and flexible molecule that can adopt a wide variety of structurally distinct states. One driving force for these rearrangements is the intrinsic ATPase activity of Hsp90, as seen with other chaperones. However, unlike other chaperones, studies have shown that the ATPase cycle of Hsp90 is not conformationally deterministic. That is, rather than dictating the conformational state, ATP binding and hydrolysis only shift the equilibria between a pre-existing set of conformational states. For bacterial, yeast and human Hsp90, there is a conserved three-state (apo–ATP–ADP) conformational cycle; however; the equilibria between states are species specific. In eukaryotes, cytosolic co-chaperones regulate the in vivo dynamic behavior of Hsp90 by shifting conformational equilibria and affecting the kinetics of structural changes and ATP hydrolysis. In this review, we discuss the structural and biochemical studies leading to our current understanding of the conformational dynamics of Hsp90, as well as the roles that nucleotide, co-chaperones, post-translational modification and substrates play. This view of Hsp90's conformational dynamics was enabled by the use of multiple complementary structural methods including, crystallography, small-angle X-ray scattering (SAXS), electron microscopy, Förster resonance energy transfer (FRET) and NMR. Finally, we discuss the effects of Hsp90 inhibitors on conformation and the potential for developing small molecules that inhibit Hsp90 by disrupting the conformational dynamics.

Type
Review Article
Information
Quarterly Reviews of Biophysics , Volume 44 , Issue 2 , May 2011 , pp. 229 - 255
Copyright
Copyright © Cambridge University Press 2011

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