Institute of Precision Medicine, National Sun Yat-sen University, Kaohsiung, Taiwan.
Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan.
Int J Biol Macromol. 2024 Jan;254(Pt 1):127566. doi: 10.1016/j.ijbiomac.2023.127566. Epub 2023 Oct 20.
The serine/threonine kinase PINK1 is responsible for phosphorylating a ubiquitin (Ub)-like domain in an E3 Ub ligase Parkin protein and a Parkin-bound Ub. PINK1 works as a mitochondrial quality control by phosphorylating and activating the E3 ubiquitin ligase Parkin. Recent medicinal study has reported that mutations of Parkin and PINK1 cause defects in mitophagy and induce early-onset Parkinson's disease (EOPD). In this study, we conducted molecular dynamics simulations to investigate the structural discrepancy caused by a clinical G409V mutation in PINK1 kinase domain's A-loop. The Ub phosphorylation begins with PINK1 D362 deprotonating the hydroxyl group of the substrate Ub's S65' and PINK1's A-loop is responsible for coordinating S65'. On contrary to G409 offering structural plasticity, the replaced, bulky V409 interferes with the alignment of D362-S65', seriously hampering Ub phosphorylation, leading to the accumulation of damaged mitochondria, and ultimately EOPD. In this study, we predicted the hPINK1-Ub binding mode and detected the structural impact brought by G409V replacement. It is expected the concluded remarks to be beneficial for developing cures to alleviate structural interference and restore PINK1 function.
丝氨酸/苏氨酸激酶 PINK1 负责磷酸化泛素（Ub）样结构域中的 E3 Ub 连接酶 Parkin 蛋白和与 Parkin 结合的 Ub。PINK1 通过磷酸化和激活 E3 泛素连接酶 Parkin 发挥线粒体质量控制作用。最近的医学研究报告称，Parkin 和 PINK1 的突变导致自噬缺陷，并引发早发性帕金森病（EOPD）。在这项研究中，我们进行了分子动力学模拟，以研究 PINK1 激酶结构域 A 环中临床 G409V 突变引起的结构差异。Ub 的磷酸化始于 PINK1 D362 去质子化底物 Ub 的 S65'上的羟基，而 PINK1 的 A 环负责协调 S65'。与提供结构可塑性的 G409 相反，取代的、庞大的 V409 干扰了 D362-S65'的对齐，严重阻碍了 Ub 的磷酸化，导致受损线粒体的积累，并最终导致 EOPD。在这项研究中，我们预测了 hPINK1-Ub 结合模式，并检测了 G409V 取代带来的结构影响。预计得出的结论将有助于开发治疗方法，以减轻结构干扰并恢复 PINK1 功能。
