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  Intrinsic inhibition of the Hsp90 ATPase activity

Richter, K., Moser, S., Hagn, F., Friedrich, R. W., Hainzl, O., Heller, M., et al. (2006). Intrinsic inhibition of the Hsp90 ATPase activity. The Journal of Biological Chemistry, 281(16), 11301-11311. doi:10.1074/jbc.M510142200.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-ED1B-E Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-ED1C-C
Genre: Journal Article
Alternative Title : Intrinsic inhibition of the Hsp90 ATPase activity

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JBiolChem_281_2006_ 11301.pdf (Any fulltext), 816KB
 
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 Creators:
Richter, Klaus, Author
Moser, Sandra, Author
Hagn, Franz, Author
Friedrich, Rainer W.1, Author              
Hainzl, Otmar, Author
Heller, Markus, Author
Schlee, Sandra2, Author              
Kessler, Horst, Author
Reinstein, Jochen2, Author              
Buchner, Johannes, Author
Affiliations:
1Department of Biomedical Optics, Max Planck Institute for Medical Research, Max Planck Society, ou_1497699              
2Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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 Abstract: The molecular chaperone Hsp90 is required for the folding and activation of a large number of substrate proteins. These are involved in essential cellular processes ranging from signal transduction to viral replication. For the activation of its substrates, Hsp90 binds and hydrolyzes ATP, which is the key driving force for conformational conversions within the dimeric chaperone. Dimerization of Hsp90 is mediated by a C-terminal dimerization site. In addition, there is a transient ATP-induced dimerization of the two N-terminal ATP-binding domains. The resulting ring-like structure is thought to be the ATPase-active conformation. Hsp90 is a slow ATPase with a turnover number of 1 ATP/min for the yeast protein. A key question for understanding the molecular mechanism of Hsp90 is how ATP hydrolysis is regulated and linked to conformational changes. In this study, we analyzed the activation process structurally and biochemically with a view to identify the conformational limitations of the ATPase reaction cycle. We showed that the first 24 amino acids stabilize the N-terminal domain in a rigid state. Their removal confers flexibility specifically to the region between amino acids 98 and 120. Most surprisingly, the deletion of this structure results in the complete loss of ATPase activity and in increased N-terminal dimerization. Complementation assays using heterodimeric Hsp90 show that this rigid lid acts as an intrinsic kinetic inhibitor of the Hsp90 ATPase cycle preventing N-terminal dimerization in the ground state. On the other hand, this structure acts, in concert with the 24 N-terminal amino acids of the other N-terminal domain, to form an activated ATPase and thus regulates the turnover number of Hsp90.

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Language(s): eng - English
 Dates: 2006-01-172005-09-152006-02-062006-02-062006-04-21
 Publication Status: Published in print
 Pages: 11
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 Table of Contents: -
 Rev. Method: Peer
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Title: The Journal of Biological Chemistry
  Other : JBC
Source Genre: Journal
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Publ. Info: Baltimore, etc. : American Society for Biochemistry and Molecular Biology [etc.]
Pages: - Volume / Issue: 281 (16) Sequence Number: - Start / End Page: 11301 - 11311 Identifier: ISSN: 0021-9258
CoNE: https://pure.mpg.de/cone/journals/resource/954925410826_1