已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整的填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

Ubiquitin is phosphorylated by PINK1 to activate parkin

帕金 品脱1 泛素 泛素连接酶 细胞生物学 粒体自噬 线粒体 生物 磷酸化 激酶 生物化学 化学 分子生物学 自噬 帕金森病 医学 细胞凋亡 疾病 病理 基因
作者
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‐François Trempe,Yasushi Saeki,Keiji Tanaka,Noriyuki Matsuda
出处
期刊:Nature [Springer Nature]
卷期号:510 (7503): 162-166 被引量:1309
标识
DOI:10.1038/nature13392
摘要

Ubiquitin, known for its role in post-translational modification of other proteins, undergoes post-translational modification itself; after a decrease in mitochondrial membrane potential, the kinase enzyme PINK1 phosphorylates ubiquitin at Ser 65, and the phosphorylated ubiquitin then interacts with ubiquitin ligase (E3) enzyme parkin, which is also phosphorylated by PINK1, and this process is sufficient for full activation of parkin enzymatic activity. The small protein ubiquitin, familiar for its role in post-translational modification of other proteins by binding to them and regulating their activity or stability, is shown here to be the substrate of the kinase PINK1, which together with the ubiquitin ligase parkin is a causal gene for hereditary recessive Parkinsonism. Noriyuki Matsuda and colleagues show that following a decrease in mitochondrial membrane potential, PINK1 phosphorylates ubiquitin at serine residue 65; the phosphorylated ubiquitin then interacts with parkin, which is also phosphorylated by PINK1. This interaction allows full activation of parkin enzymatic activity, which involves tagging mitochondrial substrates with ubiquitin. 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 Parkinsonism1,2. 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 substrates3,4,5. PINK1 acts as an upstream factor for parkin6,7 and is essential both for the activation of latent E3 parkin activity8 and for recruiting parkin onto depolarized mitochondria8,9,10,11,12. Recently, mechanistic insights into mitochondrial quality control mediated by PINK1 and parkin have been revealed3,4,5, and PINK1-dependent phosphorylation of parkin has been reported13,14,15. However, the requirement of PINK1 for parkin activation was not bypassed by phosphomimetic parkin mutation15, 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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
1秒前
未闻花名完成签到,获得积分10
4秒前
5秒前
清秋发布了新的文献求助30
5秒前
Yihvan发布了新的文献求助10
5秒前
JIE完成签到 ,获得积分10
8秒前
9秒前
受伤月饼发布了新的文献求助10
10秒前
10秒前
11秒前
zshjwk18完成签到,获得积分10
12秒前
15秒前
木木完成签到 ,获得积分10
17秒前
18秒前
18秒前
玩儿完成签到,获得积分10
19秒前
kkk关注了科研通微信公众号
21秒前
22秒前
羡雨0413发布了新的文献求助10
23秒前
zzhou7完成签到,获得积分10
23秒前
红宝发布了新的文献求助10
23秒前
勇攀高峰的科研少女完成签到 ,获得积分10
24秒前
思源应助Conran采纳,获得10
24秒前
25秒前
宋雪芹发布了新的文献求助10
27秒前
天天快乐应助咖啡续命采纳,获得10
27秒前
万能图书馆应助粗暴的达采纳,获得10
29秒前
K.I.D完成签到,获得积分10
29秒前
Lucas应助ChenYX采纳,获得10
31秒前
垚祎完成签到 ,获得积分10
31秒前
赘婿应助漂亮幻莲采纳,获得10
31秒前
星月完成签到 ,获得积分10
34秒前
井野浮应助云云采纳,获得10
35秒前
醉熏的迎天完成签到,获得积分10
38秒前
39秒前
42秒前
43秒前
44秒前
44秒前
高分求助中
歯科矯正学 第7版(或第5版) 1004
The diagnosis of sex before birth using cells from the amniotic fluid (a preliminary report) 1000
Smart but Scattered: The Revolutionary Executive Skills Approach to Helping Kids Reach Their Potential (第二版) 1000
Semiconductor Process Reliability in Practice 720
GROUP-THEORY AND POLARIZATION ALGEBRA 500
Mesopotamian divination texts : conversing with the gods : sources from the first millennium BCE 500
Days of Transition. The Parsi Death Rituals(2011) 500
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3229357
求助须知:如何正确求助?哪些是违规求助? 2877059
关于积分的说明 8197722
捐赠科研通 2544406
什么是DOI,文献DOI怎么找? 1374357
科研通“疑难数据库(出版商)”最低求助积分说明 646956
邀请新用户注册赠送积分活动 621749