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エンドウ トシヤ
ENDO TOSHIYA
遠藤 斗志也 所属 京都産業大学 生命科学部 先端生命科学科 職種 客員教授 |
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| 言語種別 | 英語 |
| 発行・発表の年月 | 2014/06 |
| 形態種別 | 研究論文 |
| 査読 | 査読あり |
| 標題 | Ubiquitin is phosphorylated by PINK1 to activate parkin |
| 執筆形態 | その他 |
| 掲載誌名 | NATURE |
| 出版社・発行元 | NATURE PUBLISHING GROUP |
| 巻・号・頁 | 510(7503),pp.162-+ |
| 著者・共著者 | Fumika Koyano,Kei Okatsu,Hidetaka Kosako,Yasushi Tamura,Etsu Go,Mayumi Kimura,Yoko Kimura,Hikaru Tsuchiya,Hidehito Yoshihara,Takatsugu Hirokawa,Toshiya Endo,Edward A. Fon,Jean-Francois Trempe,Yasushi Saeki,Keiji Tanaka,Noriyuki Matsuda |
| 概要 | PINK1 (PTEN induced putative kinase 1) and PARKIN (also known as PARK2) have been identified as the causal genes responsible for hereditary recessive early-onset Parkinsonism(1,2). PINK1 is a Ser/Thr kinase that specifically accumulates on depolarized mitochondria, whereas parkin is an E3 ubiquitin ligase that catalyses ubiquitin transfer to mitochondrial substrates(3-5). PINK1 acts as an upstream factor for parkin(6,7) and is essential both for the activation of latent E3 parkin activity(8) and for recruiting parkin onto depolarized mitochondria(8-12). Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed(3-5), and PINK1-dependent phosphorylation of parkin has been reported(13-15). However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation(15), and how PINK1 accelerates the E3 activity of parkin on damaged mitochondria is still obscure. Here we report that ubiquitin is the genuine substrate of PINK1. PINK1 phosphorylated ubiquitin at Ser 65 both in vitro and in cells, and a Ser 65 phosphopeptide derived from endogenous ubiquitin was only detected in cells in the presence of PINK1 and following a decrease in mitochondrial membrane potential. Unexpectedly, phosphomimetic ubiquitin bypassed PINK1-dependent activation of a phosphomimetic parkin mutant in cells. Furthermore, phosphomimetic ubiquitin accelerates discharge of the thioester conjugate formed by UBCH7 (also known as UBE2L3) and ubiquitin (UBCH7 ubiquitin) in the presence of parkin in vitro, indicating that it acts allosterically. The phosphorylation-dependent interaction between ubiquitin and parkin suggests that phosphorylated ubiquitin unlocks autoinhibition of the catalytic cysteine. Our results show that PINK1-dependent phosphorylation of both parkin and ubiquitin is sufficient for full activation of parkin E3 activity. These findings demonstrate that phosphorylated ubiquitin is a parkin activator. |
| DOI | 10.1038/nature13392 |
| ISSN | 0028-0836/1476-4687 |