title: Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the Co-chaperone p23.
abstract: Hsp90 is an ATP-dependent molecular chaperone. The best characterized inhibitors of Hsp90 target its ATP binding pocket, causing nonselective degradation of Hsp90 client proteins. Here, we show that the small molecule celastrol inhibits the Hsp90 chaperoning machinery by inactivating the co-chaperone p23, resulting in a more selective destabilization of steroid receptors compared with kinase clients. Our in vitro and in vivo results demonstrate that celastrol disrupts p23 function by altering its three-dimensional structure, leading to rapid formation of amyloid-like fibrils. This study reveals a unique inhibition mechanism of p23 by a small molecule that could be exploited in the dissection of protein fibrillization processes as well as in the therapeutics of steroid receptor-dependent diseases.
authors.affiliation: From the Center for Molecular Chaperone Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912. Electronic address: achadli@mcg.edu.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Chadli
authors.affiliation: the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Felts
authors.affiliation: From the Center for Molecular Chaperone Radiobiology and Cancer Virology, Medical College of Georgia, Augusta, Georgia 30912.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: William P
authors.initials: WP
authors.lastname: Sullivan
authors.affiliation: the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: Maria Victoria
authors.initials: MV
authors.lastname: Botuyan
authors.affiliation: the Organic Chemistry Laboratory, Mayo Clinic College of Medicine, Jacksonville, Florida 32224.
authors.forename: Abdul
authors.initials: A
authors.lastname: Fauq
authors.affiliation: the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.affiliation: the Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, and.
authors.forename: Georges
authors.initials: G
authors.lastname: Mer
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D016253:Microscopy, Immunoelectron; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D053978:Pentacyclic Triterpenes; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D034622:RNA Interference; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D018411:Spodoptera; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000682:Amyloid; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D053978:Pentacyclic Triterpenes; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D011994:Recombinant Proteins; D014315:Triterpenes; D000255:Adenosine Triphosphate; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C050414:celastrol