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          Institute: MPI für medizinische Forschung     Collection: Abteilung Biomolekulare Mechanismen     Display Documents



ID: 307449.0, MPI für medizinische Forschung / Abteilung Biomolekulare Mechanismen
Intrinsic inhibition of the Hsp90 ATPase activity
Translation of Title:Intrinsic inhibition of the Hsp90 ATPase activity
Authors:Richter, Klaus; Moser, Sandra; Hagn, Franz; Friedrich, Rainer; Hainzl, Otmar; Heller, Markus; Schlee, Sandra; Kessler, Horst; Reinstein, Jochen; Buchner, Johannes
Language:English
Date of Publication (YYYY-MM-DD):2006-04-21
Title of Journal:Journal of Biological Chemistry
Journal Abbrev.:J. Biol. Chem.
Volume:281
Issue / Number:16
Start Page:11301
End Page:11311
Review Status:Peer-review
Audience:Experts Only
Intended Educational Use:No
Abstract / Description: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 hydrolyses 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 Nterminal 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 per minute 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 show 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 acid 98 and 120. Surprisingly, the deletion of this structure results in the complete loss of ATPase activity and in increased Nterminal 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 âEuro“ in concert with the 24 Nterminal amino acids of the other Nterminal domain âEuro“ to form an activated ATPase and thus regulates the turnover number of Hsp90.
Last Change of the Resource (YYYY-MM-DD):--
External Publication Status:published
Document Type:Article
Communicated by:Wulf Kaiser
Affiliations:MPI für medizinische Forschung/Abteilung Biomolekulare Mechanismen
Identifiers:LOCALID:6544
URI:http://www.jbc.org/cgi/reprint/281/16/11301?maxtos...
URI:http://www.jbc.org/cgi/content/full/281/16/11301?m...
URI:http://www.jbc.org/cgi/content/abstract/281/16/113...
DOI:10.1074/jbc.M510142200
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