Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.
Asymmetric Hsp90 N domain SUMOylation recruits Aha1 and ATP-competitive inhibitors.
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DOI：
10.1016/j.molcel.2013.12.007
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发表时间：
2014-01-23
期刊：
影响因子：
16
通讯作者：
Neckers, Len
中科院分区：
文献类型：
--
作者：
Mollapour, Mehdi;Bourboulia, Dimitra;Beebe, Kristin;Woodford, Mark R.;Polier, Sigrun;Hoang, Anthony;Chelluri, Raju;Li, Yu;Guo, Allan;Lee, Min-Jung;Fotooh-Abadi, Elham;Khan, Sahar;Prince, Thomas;Miyajima, Naoto;Yoshida, Soichiro;Tsutsumi, Shinji;Xu, Wanping;Panaretou, Barry;Stetler-Stevenson, William G.;Bratslavsky, Gennady;Trepel, Jane B.;Prodromou, Chrisostomos;Neckers, Len
在正常细胞和癌细胞中，许多信号蛋白的稳定性和活性取决于二聚体分子伴侣热休克蛋白90 （Hsp90）。Hsp90的功能与ATP结合和水解相耦合，需要一系列的构象变化，这些构象变化由co-chaperones和大量的翻译后修饰（posttranslational modification, PTMs）调节。SUMOylation是最不为人所知的Hsp90 ptm之一。本研究表明，酵母（K178）和人（K191） Hsp90的n域保守赖氨酸残基的不对称SUMOylation促进了atp酶激活的共同伴侣Aha1的募集，以及意想不到的Hsp90抑制剂的结合，这表明这些药物优先与积极参与伴侣循环的Hsp90蛋白结合。重要的是，细胞转化伴随着稳态n结构域sumo化的升高，而Hsp90 sumo化的增加使酵母和哺乳动物细胞对Hsp90抑制剂敏感，这为解释癌细胞对这些药物的敏感性提供了一种机制。
The stability and activity of numerous signaling proteins in both normal and cancer cells depends on the dimeric molecular chaperone Heat Shock Protein 90 (Hsp90). Hsp90 function is coupled to ATP binding and hydrolysis, and requires a series of conformational changes that are regulated by co-chaperones and numerous posttranslational modifications (PTMs). SUMOylation is one of the least understood Hsp90 PTMs. Here we show that asymmetric SUMOylation of a conserved lysine residue in the N-domain of both yeast (K178) and human (K191) Hsp90 facilitates both recruitment of the ATPase activating co-chaperone Aha1 and, unexpectedly, the binding of Hsp90 inhibitors, suggesting that these drugs associate preferentially with Hsp90 proteins that are actively engaged in the chaperone cycle. Importantly, cellular transformation is accompanied by elevated steady-state N-domain SUMOylation and increased Hsp90 SUMOylation sensitizes yeast and mammalian cells to Hsp90 inhibitors, providing a mechanism to explain the sensitivity of cancer cells to these drugs.
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影响因子：
16
作者：
Mollapour, Mehdi;Tsutsumi, Shinji;Donnelly, Alison C.;Beebe, Kristin;Tokita, Mari J.;Lee, Min-Jung;Lee, Sunmin;Morra, Giulia;Bourboulia, Dimitra;Scroggins, Bradley T.;Colombo, Giorgio;Blagg, Brian S.;Panaretou, Barry;Stetler-Stevenson, William G.;Trepel, Jane B.;Piper, Peter W.;Prodromou, Chrisostomos;Pearl, Laurence H.;Neckers, Len
通讯作者：
Neckers, Len
影响因子：
16
作者：
Mollapour M;Tsutsumi S;Truman AW;Xu W;Vaughan CK;Beebe K;Konstantinova A;Vourganti S;Panaretou B;Piper PW;Trepel JB;Prodromou C;Pearl LH;Neckers L
通讯作者：
Neckers L
影响因子：
16.8
作者：
Hessling, Martin;Richter, Klaus;Buchner, Johannes
通讯作者：
Buchner, Johannes
影响因子：
3.3
作者：
Louvion, JF;Abbas-Terki, T;Picard, D
通讯作者：
Picard, D
DOI：
10.1016/j.bbamcr.2011.07.018
发表时间：
2012-03
影响因子：
5.1
作者：
Mollapour, Mehdi;Neckers, Len
通讯作者：
Neckers, Len