title: Threonine 22 phosphorylation attenuates Hsp90 interaction with cochaperones and affects its chaperone activity.
abstract: Heat shock protein 90 (Hsp90) is an essential molecular chaperone whose activity is regulated not only by cochaperones but also by distinct posttranslational modifications. We report here that casein kinase 2 phosphorylates a conserved threonine residue (T22) in α helix-1 of the yeast Hsp90 N-domain both in vitro and in vivo. This α helix participates in a hydrophobic interaction with the catalytic loop in Hsp90's middle domain, helping to stabilize the chaperone's ATPase-competent state. Phosphomimetic mutation of this residue alters Hsp90 ATPase activity and chaperone function and impacts interaction with the cochaperones Aha1 and Cdc37. Overexpression of Aha1 stimulates the ATPase activity, restores cochaperone interactions, and compensates for the functional defects of these Hsp90 mutants.
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mollapour
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Truman
authors.forename: Wanping
authors.initials: W
authors.lastname: Xu
authors.forename: Cara K
authors.initials: CK
authors.lastname: Vaughan
authors.forename: Kristin
authors.initials: K
authors.lastname: Beebe
authors.forename: Anna
authors.initials: A
authors.lastname: Konstantinova
authors.forename: Srinivas
authors.initials: S
authors.lastname: Vourganti
authors.forename: Barry
authors.initials: B
authors.lastname: Panaretou
authors.forename: Peter W
authors.initials: PW
authors.lastname: Piper
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018833:Chaperonins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005656:Fungal Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*
chemical_list: C475092:AHA1 protein, S cerevisiae; C513270:CDC37 protein, S cerevisiae; D018797:Cell Cycle Proteins; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D029701:Saccharomyces cerevisiae Proteins; D013912:Threonine; D047390:Casein Kinase II; D018833:Chaperonins