澳大利亚墨尔本大学David Komander课题组揭示PINK1的激活机制。2021年12月21日，《自然》杂志在线发表了这项成果。

研究人员表示，蛋白激酶PINK1的突变导致有丝分裂的缺陷，引起常染色体隐性早发性帕金森病（EOPD）。PINK1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。来自不同昆虫物种的PINK1结构分析提供了不同结构状态的快照，但并没有解释PINK1如何被激活。

研究人员通过晶体学和冷冻电镜阐明了PINK1的激活机制。未被磷酸化的体虱 (Ph) PINK1晶体结构解析了以前被遗漏的N端螺旋，揭示了未被磷酸化但具有活性的PINK1在线粒体上的定向。研究人员进一步揭示了一个2.35埃的PhPINK1二聚体冷冻电镜结构，该二聚体在反式自磷酸化过程中被困住，以及一个3.1埃的磷酸化PhPINK1的冷冻电镜结构，该结构正在经历构象变化，会成为一个活性泛素激酶。结构和磷酸化研究进一步确定了PINK1氧化的调节作用。总之，这项工作揭示了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的活性可能受到线粒体活性氧的调节。

附：英文原文

Author: Gan, Zhong Yan, Callegari, Sylvie, Cobbold, Simon A., Cotton, Thomas R., Mlodzianoski, Michael J., Schubert, Alexander F., Geoghegan, Niall D., Rogers, Kelly L., Leis, Andrew, Dewson, Grant, Glukhova, Alisa, Komander, David

Issue&Volume: 2021-12-21

Abstract: Mutations in the protein kinase PINK1 lead to defects in mitophagy and cause autosomal recessive early onset Parkinson’s Disease (EOPD)1,2. PINK1 has many unique features that enable it to phosphorylate ubiquitin and the ubiquitin-like domain of Parkin3–9. Structural analysis of PINK1 from diverse insect species10–12 with and without ubiquitin provided snapshots of distinct structural states yet did not explain how PINK1 is activated. We here elucidate the activation mechanism of PINK1 by crystallography and cryo-EM. A crystal structure of unphosphorylated Pediculus humanus corporis (Ph) PINK1 resolves a previously omitted N-terminal helix revealing how unphosphorylated yet active PINK1 is oriented on mitochondria. We further reveal a 2.35 cryo-EM structure of a symmetric PhPINK1 dimer trapped during the process of trans-autophosphorylation, and a 3.1 cryo-EM structure of phosphorylated PhPINK1 in the process of undergoing a conformational change to become an active ubiquitin kinase. Structures and phosphorylation studies further identify a role for regulatory PINK1 oxidation. Together, our work 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.

DOI: 10.1038/s41586-021-04340-2

Source: https://www.nature.com/articles/s41586-021-04340-2