State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 510060, Guangzhou, China.
Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, 300071, Tianjin, China.
Nat Commun. 2019 Oct 29;10(1):4914. doi: 10.1038/s41467-019-12912-0.
Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Mutations in MFN2 cause the neurodegenerative disease Charcot-Marie-Tooth type 2A (CMT2A). The molecular basis underlying the physiological and pathological relevance of MFN2 is unclear. Here, we present crystal structures of truncated human MFN2 in different nucleotide-loading states. Unlike other dynamin superfamily members including MFN1, MFN2 forms sustained dimers even after GTP hydrolysis via the GTPase domain (G) interface, which accounts for its high membrane-tethering efficiency. The biochemical discrepancy between human MFN2 and MFN1 largely derives from a primate-only single amino acid variance. MFN2 and MFN1 can form heterodimers via the G interface in a nucleotide-dependent manner. CMT2A-related mutations, mapping to different functional zones of MFN2, lead to changes in GTP hydrolysis and homo/hetero-association ability. Our study provides fundamental insight into how mitofusins mediate mitochondrial fusion and the ways their disruptions cause disease.
线粒体融合蛋白 2（MFN2）是一种类似于动力蛋白的 GTP 酶，在调节线粒体融合和细胞代谢中发挥核心作用。MFN2 中的突变会导致神经退行性疾病 2A 型腓骨肌萎缩症（CMT2A）。MFN2 的生理和病理相关性的分子基础尚不清楚。在这里，我们呈现了不同核苷酸加载状态下截短的人 MFN2 的晶体结构。与包括 MFN1 在内的其他动力蛋白超家族成员不同，MFN2 甚至在 GTP 水解后通过 GTP 酶结构域（G）界面形成持续的二聚体，这解释了其高膜结合效率。人类 MFN2 和 MFN1 之间的生化差异主要源于灵长类动物特有的单个氨基酸变异。MFN2 和 MFN1 可以通过 G 界面以核苷酸依赖的方式形成异源二聚体。CMT2A 相关突变，映射到 MFN2 的不同功能区，导致 GTP 水解和同/异源缔合能力的变化。我们的研究为线粒体融合蛋白如何介导线粒体融合以及它们的破坏如何导致疾病提供了基本的见解。
