An Hsp90 co-chaperone protein in yeast is functionally replaced by site-specific posttranslational modification in humans

Abbey D. Zuehlke, Michael Reidy, Coney Lin, Paul LaPointe, Sarah Alsomairy, D. Joshua Lee, Genesis M. Rivera-Marquez, Kristin Beebe, Thomas Prince, Sunmin Lee, Jane B. Trepel, Wanping Xu, Jill Johnson, Daniel Masison and Len Neckers ()
Additional contact information
Abbey D. Zuehlke: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Michael Reidy: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Coney Lin: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Paul LaPointe: Faculty of Medicine and Dentistry, University of Alberta
Sarah Alsomairy: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
D. Joshua Lee: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Genesis M. Rivera-Marquez: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Kristin Beebe: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Thomas Prince: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Sunmin Lee: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
Jane B. Trepel: Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute
Wanping Xu: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute
Jill Johnson: University of Idaho
Daniel Masison: Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Len Neckers: Urologic Oncologic Branch, Center for Cancer Research, National Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Heat shock protein 90 (Hsp90) is an essential eukaryotic molecular chaperone. To properly chaperone its clientele, Hsp90 proceeds through an ATP-dependent conformational cycle influenced by posttranslational modifications (PTMs) and assisted by a number of co-chaperone proteins. Although Hsp90 conformational changes in solution have been well-studied, regulation of these complex dynamics in cells remains unclear. Phosphorylation of human Hsp90α at the highly conserved tyrosine 627 has previously been reported to reduce client interaction and Aha1 binding. Here we report that these effects are due to a long-range conformational impact inhibiting Hsp90α N-domain dimerization and involving a region of the middle domain/carboxy-terminal domain interface previously suggested to be a substrate binding site. Although Y627 is not phosphorylated in yeast, we demonstrate that the non-conserved yeast co-chaperone, Hch1, similarly affects yeast Hsp90 (Hsp82) conformation and function, raising the possibility that appearance of this PTM in higher eukaryotes represents an evolutionary substitution for HCH1.

Date: 2017
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DOI: 10.1038/ncomms15328

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