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J Mol Biol. 2014 Jun 12;426(12):2393-404. doi: 10.1016/j.jmb.2014.04.001. Epub 2014 Apr 12.

Elucidating the mechanism of substrate recognition by the bacterial Hsp90 molecular chaperone.

Author information

  • 1Department of Biochemistry, Brandeis University, Waltham, MA 02453, USA. Electronic address: tstreet@brandeis.edu.
  • 2Department of Molecular, Cellular, and Biomedical Sciences, University of New Hampshire, Durham, NH 03824, USA.
  • 3Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158, USA.
  • 4Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
  • 5Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA; The Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA.

Abstract

Hsp90 is a conformationally dynamic molecular chaperone known to promote the folding and activation of a broad array of protein substrates ("clients"). Hsp90 is believed to preferentially interact with partially folded substrates, and it has been hypothesized that the chaperone can significantly alter substrate structure as a mechanism to alter the substrate functional state. However, critically testing the mechanism of substrate recognition and remodeling by Hsp90 has been challenging. Using a partially folded protein as a model system, we find that the bacterial Hsp90 adapts its conformation to the substrate, forming a binding site that spans the middle and C-terminal domains of the chaperone. Cross-linking and NMR measurements indicate that Hsp90 binds to a large partially folded region of the substrate and significantly alters both its local and long-range structure. These findings implicate Hsp90's conformational dynamics in its ability to bind and remodel partially folded proteins. Moreover, native-state hydrogen exchange indicates that Hsp90 can also interact with partially folded states only transiently populated from within a thermodynamically stable, native-state ensemble. These results suggest a general mechanism by which Hsp90 can recognize and remodel native proteins by binding and remodeling partially folded states that are transiently sampled from within the native ensemble.

KEYWORDS:

Hsp90; HtpG; chaperone; protein folding

PMID:
24726919
DOI:
10.1016/j.jmb.2014.04.001
[PubMed - indexed for MEDLINE]
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