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Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90? Function in Yeast.

ABSTRACT: Hsp90 is a highly conserved molecular chaperone important for the activity of many client proteins. Hsp90 has an N-terminal ATPase domain (N), a middle domain (M) that interacts with clients and a C-terminal dimerization domain (C). "Closing" of dimers around clients is regulated by ATP binding, co-chaperones, and post-translational modifications. ATP hydrolysis coincides with release of mature client and resetting the reaction cycle. Humans have two Hsp90s: hHsp90? and hHsp90?. Although 85% identical, hHsp90? supports Hsp90 function in yeast much better than hHsp90?. Determining the basis of this difference would provide important insight into functional specificity of seemingly redundant Hsp90s, and the evolution of eukaryotic Hsp90 systems and clientele. Here, we found host co-chaperones Sba1, Cpr6 and Cpr7 inhibited hHsp90? function in yeast, and we identified mutations clustering in the N domain that considerably improved hHsp90? function in yeast. The strongest of these rescuer mutations accelerated nucleotide-dependent lid closing, N-M domain docking, and ATPase. It also disrupted binding to Sba1, which prolongs the closed state, and promoted N-M undocking and lid opening. Our data suggest the rescuer mutations improve function of hHsp90? in yeast by accelerating return to the open state. Our findings imply hHsp90? occupies the closed state too long to function effectively in yeast, and define an evolutionarily conserved region of the N domain involved in resetting the Hsp90 reaction cycle.

SUBMITTER: Reidy M

PROVIDER: S-EPMC7437358 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90α Function in Yeast.

Reidy Michael M Masison Daniel C DC

Journal of molecular biology 20200619 16

Hsp90 is a highly conserved molecular chaperone important for the activity of many client proteins. Hsp90 has an N-terminal ATPase domain (N), a middle domain (M) that interacts with clients and a C-terminal dimerization domain (C). "Closing" of dimers around clients is regulated by ATP binding, co-chaperones, and post-translational modifications. ATP hydrolysis coincides with release of mature client and resetting the reaction cycle. Humans have two Hsp90s: hHsp90α and hHsp90β. Although 85% ide ...[more]

PMID: 32565117

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Dataset Information

Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90? Function in Yeast.

Publications

Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90α Function in Yeast.

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