Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset

• Published in: Nature communications Vol. 10; no. 1; pp. 4914 - 14
• Main Authors: Li, Yu-Jie, Cao, Yu-Lu, Feng, Jian-Xiong, Qi, Yuanbo, Meng, Shuxia, Yang, Jie-Feng, Zhong, Ya-Ting, Kang, Sisi, Chen, Xiaoxue, Lan, Lan, Luo, Li, Yu, Bing, Chen, Shoudeng, Chan, David C., Hu, Junjie, Gao, Song
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 38/70; 631/45/173; 631/535/1266; 631/80/642/333; 692/699/375/365; 82/80; 82/83; Amino acids; Cell fusion; Charcot-Marie-Tooth disease; Charcot-Marie-Tooth Disease - enzymology; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - physiopathology; Crystal structure; Dimerization; Dimers; Dynamin; GTP Phosphohydrolases - chemistry; GTP Phosphohydrolases - genetics; GTP Phosphohydrolases - metabolism; Guanosine triphosphatases; Guanosine triphosphate; Guanosine Triphosphate - metabolism; Humanities and Social Sciences; Humans; Hydrolysis; Mapping; Mitochondria; Mitochondria - chemistry; Mitochondria - enzymology; Mitochondria - genetics; Mitochondrial Dynamics; Mitochondrial Membrane Transport Proteins - chemistry; Mitochondrial Membrane Transport Proteins - genetics; Mitochondrial Membrane Transport Proteins - metabolism; Mitochondrial Proteins - chemistry; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; multidisciplinary; Mutation; Neurodegenerative diseases; Nucleotides; Protein Domains; Science; Science (multidisciplinary); Tethering
• DOI: 10.1038/s41467-019-12912-0
• ISSN: 2041-1723

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. Mitofusin-2 (MFN2) is a dynamin-like GTPase that plays a central role in regulating mitochondrial fusion and cell metabolism. Here, authors report crystal structures of truncated human MFN2 in different nucleotide-loading states and show that MFN2 forms sustained dimers even after GTP hydrolysis.