2AKP

Hsp90 Delta24-N210 mutant

Summary for 2AKP

• Entry DOI: 10.2210/pdb2akp/pdb
• Descriptor: ATP-dependent molecular chaperone HSP82 (2 entities in total)
• Functional Keywords: hsp90, xray crystal structure, intrinsic inhibition, chaperone
• Biological source: Saccharomyces cerevisiae (baker's yeast)
• Cellular location: Cytoplasm: P02829
• Total number of polymer chains: 2
• Total formula weight: 41919.75

Authors

Richter, K.,Moser, S.,Hagn, F.,Friedrich, R.,Hainzl, O.,Heller, M.,Schlee, S.,Kessler, H.,Reinstein, J.,Buchner, J. (deposition date: 2005-08-03, release date: 2006-01-31, Last modification date: 2023-08-23)

Primary citation

Richter, K.,Moser, S.,Hagn, F.,Friedrich, R.,Hainzl, O.,Heller, M.,Schlee, S.,Kessler, H.,Reinstein, J.,Buchner, J.
Intrinsic inhibition of the Hsp90 ATPase activity.
J.Biol.Chem., 281:11301-11311, 2006

PubMed 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.

PubMed: 16461354
DOI: 10.1074/jbc.M510142200

Experimental method

X-RAY DIFFRACTION (1.94 Å)