Mutations in the Hsp90 N Domain Identify a Site that Controls Dimer Opening and Expand Human Hsp90α Function in Yeast
| Autor: | Michael Reidy, Daniel C. Masison |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Saccharomyces cerevisiae Proteins ATPase Dimer Hsp90 Saccharomyces cerevisiae Article 03 medical and health sciences chemistry.chemical_compound Closed state Sba1 0302 clinical medicine Adenosine Triphosphate Protein Domains Structural Biology ATP hydrolysis Humans HSP90 Heat-Shock Proteins Cloning Molecular Hsp90 beta Molecular Biology 030304 developmental biology 0303 health sciences Binding Sites biology Hsp82 Yeast Cell biology A-site chemistry Gene Expression Regulation Docking (molecular) Mutation biology.protein Hsp90 alpha 030217 neurology & neurosurgery Cyclophilin D Molecular Chaperones Protein Binding |
| Zdroj: | Journal of molecular biology |
| ISSN: | 1089-8638 |
| Popis: | 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% identical, hHsp90β supports Hsp90 function in yeast much better than hHsp90α. 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 hHsp90α function in yeast, and we identified mutations clustering in the N domain that considerably improved hHsp90α 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 hHsp90α in yeast by accelerating return to the open state. Our findings imply hHsp90α 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect