Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the Co-chaperone p23.
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.
Mesh Terms:
Adenosine Triphosphate, Amyloid, Animals, Blotting, Western, Cell Line, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Intramolecular Oxidoreductases, Magnetic Resonance Spectroscopy, Microscopy, Immunoelectron, Models, Molecular, Molecular Chaperones, Mutagenesis, Site-Directed, Protein Binding, Protein Conformation, Protein Multimerization, RNA Interference, Receptors, Progesterone, Receptors, Steroid, Recombinant Proteins, Spodoptera, Triterpenes
Adenosine Triphosphate, Amyloid, Animals, Blotting, Western, Cell Line, HSP90 Heat-Shock Proteins, HeLa Cells, Humans, Intramolecular Oxidoreductases, Magnetic Resonance Spectroscopy, Microscopy, Immunoelectron, Models, Molecular, Molecular Chaperones, Mutagenesis, Site-Directed, Protein Binding, Protein Conformation, Protein Multimerization, RNA Interference, Receptors, Progesterone, Receptors, Steroid, Recombinant Proteins, Spodoptera, Triterpenes
J. Biol. Chem.
Date: Feb. 05, 2010
PubMed ID: 19996313
View in: Pubmed Google Scholar
Download Curated Data For This Publication
195438
Switch View:
- Interactions 2