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Dynamics of heat shock protein 90 C-terminal dimerization is an important part of its conformational cycle
Edited by George H. Lorimer, University of Maryland, College Park, MD, and approved July 22, 2010 (received for review January 26, 2010)

Abstract
The molecular chaperone heat shock protein 90 (Hsp90) is an important and abundant protein in eukaryotic cells, essential for the activation of a large set of signal transduction and regulatory proteins. During the functional cycle, the Hsp90 dimer performs large conformational rearrangements. The transient N-terminal dimerization of Hsp90 has been extensively investigated, under the assumption that the C-terminal interface is stably dimerized. Using a fluorescence-based single molecule assay and Hsp90 dimers caged in lipid vesicles, we were able to separately observe and kinetically analyze N- and C-terminal dimerizations. Surprisingly, the C-terminal dimer opens and closes with fast kinetics. The occupancy of the unexpected C-terminal open conformation can be modulated by nucleotides bound to the N-terminal domain and by N-terminal deletion mutations, clearly showing a communication between the two terminal domains. Moreover our findings suggest that the C- and N-terminal dimerizations are anticorrelated. This changes our view on the conformational cycle of Hsp90 and shows the interaction of two dimerization domains.
Footnotes
- 1To whom correspondence should be addressed. E-mail: thorsten.hugel{at}ph.tum.de.
Author contributions: J.B. and T.H. designed research; C.R., M.M., and B.H. performed research; C.R., M.M., B.H., and T.H. analyzed data; and C.R., M.M., J.B., and T.H. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1000916107/-/DCSupplemental.