Structure and mechanism of the Hsp90 molecular chaperone machinery.

By L. Pearl, C. Prodromou. Annual Review of Biochemistry, 2006

1,112 citations recorded by the source corpus.

Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell. Biochemical and structural analysis of Hsp90 has revealed a complex mechanism of ATPase-coupled conformational changes and interactions with cochaperone proteins, which facilitate activation of Hsp90's diverse "clientele." Despite recent progress, key aspects of the ATPase-coupled mechanism of Hsp90 remain controversial, and the nature of the changes, engendered by Hsp90 in client proteins, is largely unknown. Here, we discuss present knowledge of Hsp90 structure and function gleaned from crystallographic studies of individual domains and recent progress in obtaining a structure for the ATP-bound conformation of the intact dimeric chaperone. Additionally, we describe the roles of the plethora of cochaperones with which Hsp90 cooperates and growing insights into their biochemical mechanisms, which come from crystal structures of Hsp90 cochaperone complexes.

Subfields: Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/3e82b77f7c2b30f237cc95384f56d65fa4573aae

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In Materials Chemistry

1. Susan Lindquist

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3. Mikko Taipale
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Citations in the corpus

• Targeting the dynamic HSP90 complex in cancer (2010, background): “Conformational flexibility of HSP90 HSP90 is a member of a small superfamily of functionally unrelated proteins (that also comprises DNA gyrase, histidine kinase and the DNA mismatch repair protein MutL) that possess a unique ATP-binding pocket that is distinct from the ATP-binding cleft of protei”
• Biological Insights from Structures of Two-Component Proteins (2009, background): “Therefore, the conformational changes of the ATP-lid are proposed to couple the ATP binding to alterations of interdomain or protein-protein interactions for regulation, as seen in other GHL ATPase family members (71).”
• Recent advances in the development of protein–protein interactions modulators: mechanisms and clinical trials (2020, background): “The C-terminal domain is a self-dimerization site of Hsp90, which enhances the interaction of two Hsp90 N-terminal domains.(114) The current Hsp90 inhibitors can be classified into three categories: the N-terminal ATP pocket inhibitors, the C-terminal nucleotide site inhibitors, the Hsp90 and Fig.”
• Lysine acetylation: codified crosstalk with other posttranslational modifications (2008, background): “segment for client protein recognition, and a C-terminal domain essential for Hsp90 dimerization (Pearl and Prodromou, 2006).”
• HSP90 at the hub of protein homeostasis: emerging mechanistic insights (2010, background): “HSP90 shares structural homology with other ATPases in the GHKL (gyrase, HSP90, histidine kinase and MutL) superfamil”
• Successful applications of computer aided drug discovery: moving drugs from concept to the clinic. (2010, background): “The molecular chaperone heat shock protein 90 (HSP90) supports the correct conformation, stabilization, activation, and localization of ‘‘client’’ proteins, many of which are involved in tumor progression, hence HSP90 is an ideal and novel target in cancer therapy [71-74].”