Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination.
Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination.
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DOI：
10.1021/bi200175q
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发表时间：
2011-05-10
期刊：
影响因子：
2.9
通讯作者：
Gurevich EV
中科院分区：
文献类型：
--
作者：
Ahmed MR;Zhan X;Song X;Kook S;Gurevich VV;Gurevich EV
E3泛素连接酶parkin的许多突变被证明与家族性帕金森病有关。在这里，我们表明，帕金结合抑制蛋白，细胞信号的多功能调节器。抑制蛋白-帕金相互作用通过来自脑组织的内源性蛋白质的共免疫沉淀来证明，并且使用纯化的蛋白质显示为直接的。Parkin结合增强了抑制蛋白与另一种E3泛素连接酶Mdm 2的相互作用，显然是通过将抑制蛋白构象平衡转移到Mdm 2偏好的基础状态。虽然Mdm 2被报道为泛素化抑制蛋白，但Mdm 2结合的parkin依赖性增加显著降低了非视觉抑制蛋白的泛素化，基础的和受受体激活刺激的，而不影响受体内化。几种疾病相关的帕金突变差异影响Mdm 2结合的刺激。所有测试的parkin突变体有效地抑制arrestin泛素化，表明结合parkin屏蔽了Mdm 2靶向的arrestin赖氨酸。帕金结合抑制蛋白沿着其对抑制蛋白与Mdm 2的相互作用和泛素化的影响是这种蛋白质的新功能，其对帕金森病病理学具有意义。
Numerous mutations in E3 ubiquitin ligase parkin were shown to associate with familial Parkinson's disease. Here we show that parkin binds arrestins, versatile regulators of cell signaling. Arrestin-parkin interaction was demonstrated by coimmuno-precipitation of endogenous proteins from brain tissue, and shown to be direct using purified proteins. Parkin binding enhances arrestin interactions with another E3 ubiquitin ligase, Mdm2, apparently by shifting arrestin conformational equilibrium to the basal state preferred by Mdm2. Although Mdm2 was reported to ubiquitinate arrestins, parkin-dependent increase in Mdm2 binding dramatically reduces the ubiquitination of both non-visual arrestins, basal and stimulated by receptor activation, without affecting receptor internalization. Several disease-associated parkin mutations differentially affect the stimulation of Mdm2 binding. All parkin mutants tested effectively suppress arrestin ubiquitination, suggesting that bound parkin shields arrestin lysines targeted by Mdm2. Parkin binding to arrestins along with its effects on arrestin interaction with Mdm2 and ubiquitination is a novel function of this protein with implications for Parkinson's disease pathology.
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影响因子：
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作者：
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