帕金
泛素
品脱1
生物
免疫沉淀
磷酸化
细胞生物学
线粒体
泛素连接酶
自噬
粒体自噬
溶酶体
生物化学
帕金森病
基因
内科学
疾病
酶
细胞凋亡
医学
作者
Kei Okatsu,Fumika Koyano,Mayumi Kimura,Hidetaka Kosako,Yasushi Saeki,Keiji Tanaka,Noriyuki Matsuda
标识
DOI:10.1083/jcb.201410050
摘要
PINK1 selectively recruits Parkin to depolarized mitochondria for quarantine and removal of damaged mitochondria via ubiquitylation. Dysfunction of this process predisposes development of familial recessive Parkinson's disease. Although various models for the recruitment process have been proposed, none of them adequately explain the accumulated data, and thus the molecular basis for PINK1 recruitment of Parkin remains to be fully elucidated. In this study, we show that a linear ubiquitin chain of phosphomimetic tetra-ubiquitin(S65D) recruits Parkin to energized mitochondria in the absence of PINK1, whereas a wild-type tetra-ubiquitin chain does not. Under more physiologically relevant conditions, a lysosomal phosphorylated polyubiquitin chain recruited phosphomimetic Parkin to the lysosome. A cellular ubiquitin replacement system confirmed that ubiquitin phosphorylation is indeed essential for Parkin translocation. Furthermore, physical interactions between phosphomimetic Parkin and phosphorylated polyubiquitin chain were detected by immunoprecipitation from cells and in vitro reconstitution using recombinant proteins. We thus propose that the phosphorylated ubiquitin chain functions as the genuine Parkin receptor for recruitment to depolarized mitochondria.
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