TY - JOUR
T1 - Celastrol inhibits Hsp90 chaperoning of steroid receptors by inducing fibrillization of the co-chaperone p23
AU - Chadli, Ahmed
AU - Felts, Sara J.
AU - Wang, Qin
AU - Sullivan, William P.
AU - Botuyan, Maria Victoria
AU - Fauq, Abdul
AU - Ramirez-Alvarado, Marina
AU - Mer, Georges
PY - 2010/2/5
Y1 - 2010/2/5
N2 - 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-chaper-one 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.
AB - 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-chaper-one 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.
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U2 - 10.1074/jbc.M109.081018
DO - 10.1074/jbc.M109.081018
M3 - Article
C2 - 19996313
AN - SCOPUS:77950485584
SN - 0021-9258
VL - 285
SP - 4224
EP - 4231
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -