title: Analysis of Hsp90 cochaperone interactions reveals a novel mechanism for TPR protein recognition.
abstract: The chaperone Hsp90 is required for the appropriate regulation of numerous key signaling molecules, including the progesterone receptor (PR). Many important cochaperones bind Hsp90 through their tetratricopeptide repeat (TPR) domains. Two such proteins, GCUNC45 and FKBP52, assist PR chaperoning and are thought to interact sequentially with PR-Hsp90 complexes. TPR proteins bind to the C-terminal MEEVD sequence of Hsp90, but GCUNC45 has been shown also to bind to a novel site near the N-terminus. We now show that FKBP52 is also able to bind to this site, and that these two cochaperones act competitively, through Hsp90, to modulate PR activity. The N-terminal site involves noncontiguous amino acids within or near the ATP binding pocket of Hsp90. TPR interactions at this site are thus strongly regulated by nucleotide binding and Hsp90 conformation. We propose an expanded model for client chaperoning in which the coordinated use of TPR recognition sites at both N- and C-terminal ends of Hsp90 enhances its ability to coordinate interactions with multiple TPR partners.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. chadli.ahmed@mayo.edu
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chadli
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Bruinsma
authors.forename: Bridget
authors.initials: B
authors.lastname: Stensgard
authors.forename: David
authors.initials: D
authors.lastname: Toft
mesh_terms: D001665:Binding Sites; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011980:Receptors, Progesterone / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D011980:Receptors, Progesterone; C509158:UNC45A protein, human; D022021:Tacrolimus Binding Proteins; C403485:tacrolimus binding protein 4