Activation mechanism of PINK1.
Activation mechanism of PINK1.
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PINK1的激活机制
DOI：
10.1038/s41586-021-04340-2
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Komander D
中科院分区：
文献类型：
--
作者：
Gan ZY;Callegari S;Cobbold SA;Cotton TR;Mlodzianoski MJ;Schubert AF;Geoghegan ND;Rogers KL;Leis A;Dewson G;Glukhova A;Komander D
蛋白激酶PINK1的突变会导致有丝分裂的缺陷，并导致常染色体隐性遗传的早发性帕金森病。PINK1具有许多独特的功能，使其能够磷酸化泛素和Parkin的泛素样结构域。对含有和不含有泛素的不同昆虫物种的PINK1的结构分析提供了不同结构状态的快照，但没有解释PINK1是如何被激活的。在这里，我们用结晶学和低温电子显微镜(Cryo-EM)阐明了PINK1的激活机制。非磷酸化的人鞭毛虫(Ph；人体虱子)PINK1的晶体结构解析了N端的螺旋，揭示了线粒体上未磷酸化但具有活性的PINK1的方向。我们进一步提供了在反式自磷酸化过程中捕获的对称PhPINK1二聚体的低温EM结构，以及经历构象变化到活性泛素激酶状态的磷酸化PhPINK1的低温EM结构。结构和磷酸化研究进一步确定了PINK1氧化的调节作用。综上所述，我们的研究揭示了PINK1的完整激活机制，阐明了PINK1如何与线粒体外膜相互作用，并揭示了PINK1活性可能如何受到线粒体活性氧的调节。未磷酸化的PINK1在经历反式自磷酸化之前形成二聚化状态，而磷酸化的PINK1在N-叶发生构象变化，产生其磷酸化的泛素结合状态。
Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson’s disease. PINK1 has many unique features that enable it to phosphorylate ubiquitin and the ubiquitin-like domain of Parkin. Structural analysis of PINK1 from diverse insect species with and without ubiquitin provided snapshots of distinct structural states yet did not explain how PINK1 is activated. Here we elucidate the activation mechanism of PINK1 using crystallography and cryo-electron microscopy (cryo-EM). A crystal structure of unphosphorylated Pediculus humanus corporis (Ph; human body louse) PINK1 resolves an N-terminal helix, revealing the orientation of unphosphorylated yet active PINK1 on the mitochondria. We further provide a cryo-EM structure of a symmetric PhPINK1 dimer trapped during the process of trans-autophosphorylation, as well as a cryo-EM structure of phosphorylated PhPINK1 undergoing a conformational change to an active ubiquitin kinase state. Structures and phosphorylation studies further identify a role for regulatory PINK1 oxidation. Together, our research delineates the complete activation mechanism of PINK1, illuminates how PINK1 interacts with the mitochondrial outer membrane and reveals how PINK1 activity may be modulated by mitochondrial reactive oxygen species. Unphosphorylated PINK1 of Pediculus humanus corporis forms a dimerized state before undergoing trans-autophosphorylation, and phosphorylated PINK1 undergoes a conformational change in the N-lobe to produce its phosphorylated, ubiquitin-binding state.
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影响因子：
64.8
作者：
Gladkova C;Maslen SL;Skehel JM;Komander D
通讯作者：
Komander D
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
2.5
作者：
Aragão D;Aishima J;Cherukuvada H;Clarken R;Clift M;Cowieson NP;Ericsson DJ;Gee CL;Macedo S;Mudie N;Panjikar S;Price JR;Riboldi-Tunnicliffe A;Rostan R;Williamson R;Caradoc-Davies TT
通讯作者：
Caradoc-Davies TT
DOI：
10.1083/jcb.201402104
发表时间：
2014-04-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kane LA;Lazarou M;Fogel AI;Li Y;Yamano K;Sarraf SA;Banerjee S;Youle RJ
通讯作者：
Youle RJ
DOI：
10.1107/s0907444909042073
发表时间：
2010-01
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Chen VB;Arendall WB 3rd;Headd JJ;Keedy DA;Immormino RM;Kapral GJ;Murray LW;Richardson JS;Richardson DC
通讯作者：
Richardson DC