GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1
GrpE-like regulation of the Hsc70 chaperone by the anti-apoptotic protein BAG-1
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DOI：
10.1093/emboj/16.20.6209
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发表时间：
1997-10-15
期刊：
影响因子：
11.4
通讯作者：
Jentsch, S
中科院分区：
文献类型：
--
作者：
Hohfeld, J;Jentsch, S
BAG-1蛋白似乎通过与Bcl-2、Raf-I蛋白激酶和某些生长因子受体结合来抑制细胞死亡，但抑制机制仍然是谜。BAG-1还与几种类固醇激素受体相互作用，这些受体需要分子伴侣Hsc 70和Hsp 90来激活。在这里，我们表明BAG-1是Hsc 70伴侣的调节剂，BAG-1与Hsc 70的ATP酶结构域结合，并与Hsp 40合作，刺激Hsc 70的稳态ATP水解活性接近40倍。与GrpE蛋白对细菌Hsp 70的作用类似，BAG-1加速ADP从Hsc 70的释放，因此，BAG-1以与Hsc 70相互作用蛋白Hip相反的方式调节Hsc 70 ATP酶，Hip稳定ADP结合状态。有趣的是，BAG-1和Hip竞争结合Hsc 70的ATP酶结构域。我们的结果揭示了Hsc 70调节的意外多样性，并提出了观察到的BAG-1的抗凋亡功能可能通过调节Hsc 70对特定蛋白质折叠和成熟途径的伴侣活性来发挥的可能性。
The BAG-1 protein appears to inhibit cell death by binding to Bcl-2, the Raf-l protein kinase, and certain growth factor receptors, but the mechanism of inhibition remains enigmatic, BAG-1 also interacts with several steroid hormone receptors which require the molecular chaperones Hsc70 and Hsp90 for activation, Here we show that BAG-1 is a regulator of the Hsc70 chaperone, BAG-1 binds to the ATPase domain of Hsc70 and, in cooperation with Hsp40, stimulates Hsc70's steady-state ATP hydrolysis activity similar to 40-fold, Similar to the action of the GrpE protein on bacterial Hsp70, BAG-1 accelerates the release of ADP from Hsc70, Thus, BAG-1 regulates the Hsc70 ATPase in a manner contrary to the Hsc70-interacting protein Hip, which stabilizes the ADP-bound state. Intriguingly, BAG-1 and Hip compete in binding to the ATPase domain of Hsc70, Our results reveal an unexpected diversity in the regulation of Hsc70 and raise the possibility that the observed anti-apoptotic function of BAG-1 may be exerted through a modulation of the chaperone activity of Hsc70 on specific protein folding and maturation pathways.