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

被引:121
作者
Li, Yu-Jie [1 ]
Cao, Yu-Lu [1 ]
Feng, Jian-Xiong [1 ]
Qi, Yuanbo [2 ]
Meng, Shuxia [3 ]
Yang, Jie-Feng [1 ]
Zhong, Ya-Ting [1 ]
Kang, Sisi [4 ]
Chen, Xiaoxue [4 ]
Lan, Lan [5 ,6 ]
Luo, Li [1 ]
Yu, Bing [1 ]
Chen, Shoudeng [4 ]
Chan, David C. [3 ]
Hu, Junjie [2 ,5 ,6 ]
Gao, Song [1 ,7 ]
机构
[1] Sun Yat Sen Univ, Canc Ctr, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China
[2] Nankai Univ, Coll Life Sci, Dept Genet & Cell Biol, Tianjin 300071, Peoples R China
[3] CALTECH, Div Biol & Biol Engn, Pasadena, CA 91125 USA
[4] Sun Yat Sen Univ, Affiliated Hosp 5, Guangdong Prov Key Lab Biomed Imaging, Dept Expt Med, Zhuhai 519000, Peoples R China
[5] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing 100101, Peoples R China
[6] Univ Chinese Acad Sci, Beijing 100101, Peoples R China
[7] Guangzhou Regenerat Med & Hlth Guangdong Lab, Guangzhou 510530, Guangdong, Peoples R China
基金
国家重点研发计划; 中国国家自然科学基金; 美国国家卫生研究院;
关键词
ENDOPLASMIC-RETICULUM; PROVIDE INSIGHT; 2; MFN2; FISSION; DIMERIZATION; PARKIN; MUTATIONS; PROMOTES; DEFECTS; TOOLS;
D O I
10.1038/s41467-019-12912-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
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页数:14
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