title: The co-chaperone Hch1 regulates Hsp90 function differently than its homologue Aha1 and confers sensitivity to yeast to the Hsp90 inhibitor NVP-AUY922.
abstract: Hsp90 is a dimeric ATPase responsible for the activation or maturation of a specific set of substrate proteins termed 'clients'. This molecular chaperone acts in the context of a structurally dynamic and highly regulated cycle involving ATP, co-chaperone proteins and clients. Co-chaperone proteins regulate conformational transitions that may be impaired in mutant forms of Hsp90. We report here that the in vivo impairment of commonly studied Hsp90 variants harbouring the G313S or A587T mutation are exacerbated by the co-chaperone Hch1p. Deletion of HCH1, but not AHA1, mitigates the temperature sensitive phenotype and high sensitivity to Hsp90 inhibitor drugs observed in Saccharomyces cerevisiae that express either of these two Hsp90 variants. Moreover, the deletion of HCH1 results in high resistance to Hsp90 inhibitors in yeast that express wildtype Hsp90. Conversely, the overexpression of Hch1p greatly increases sensitivity to Hsp90 inhibition in yeast expressing wildtype Hsp90. We conclude that despite the similarity between these two co-chaperones, Hch1p and Aha1p regulate Hsp90 function in distinct ways and likely independent of their roles as ATPase stimulators. We further conclude that Hch1p plays a critical role in regulating Hsp90 inhibitor drug sensitivity in yeast.
authors.affiliation: Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Armstrong
authors.forename: Annemarie
authors.initials: A
authors.lastname: Wolmarans
authors.forename: Rebecca
authors.initials: R
authors.lastname: Mercier
authors.forename: BaoChan
authors.initials: B
authors.lastname: Mai
authors.forename: Paul
authors.initials: P
authors.lastname: LaPointe
mesh_terms: D000595:Amino Acid Sequence; D015153:Blotting, Western; D018833:Chaperonins / Q000378:metabolism*; D017353:Gene Deletion; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007555:Isoxazoles / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D012118:Resorcinols / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; C475092:AHA1 protein, S cerevisiae; C117748:HCH1 protein, S cerevisiae; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D018832:Molecular Chaperones; D012118:Resorcinols; D029701:Saccharomyces cerevisiae Proteins; D018833:Chaperonins