Ubiquitin Ligase Parkin Promotes Mdm2鈥揂rrestin Interaction but Inhibits Arrestin Ubiquitination

详细信息    查看全文

• 作者：M. Rafiuddin Ahmed ; Xuanzhi Zhan ; Xiufeng Song ; Seunghyi Kook ; Vsevolod V. Gurevich ; Eugenia V. Gurevich
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：May 10, 2011
• 年：2011
• 卷：50
• 期：18
• 页码：3749-3763
• 全文大小：1367K
• 年卷期：v.50,no.18(May 10, 2011)
• ISSN：1520-4995

文摘

Numerous mutations in E3 ubiquitin ligase parkin were shown to associate with familial Parkinson鈥檚 disease. Here we show that parkin binds arrestins, versatile regulators of cell signaling. Arrestin鈥損arkin interaction was demonstrated by coimmunoprecipitation 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 nonvisual 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鈥檚 disease pathology.