Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
Yu-Jie Li, Yu-Lu Cao, Jian-Xiong Feng, Yuanbo Qi, Shuxia Meng, Jie-Feng Yang, Ya-Ting Zhong, Sisi Kang, Xiaoxue Chen, Lan Lan, Li Luo, Bing Yu, Shoudeng Chen, David C. Chan, Junjie Hu & Song Gao
Abstract
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.
附件下载：
Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset, Nature Comm, 29 Oct 2019
Nature Communications, 29 October, 2019，DOI：https://doi.org/10.1038/s41467-019-12912-0
Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset
Yu-Jie Li, Yu-Lu Cao, Jian-Xiong Feng, Yuanbo Qi, Shuxia Meng, Jie-Feng Yang, Ya-Ting Zhong, Sisi Kang, Xiaoxue Chen, Lan Lan, Li Luo, Bing Yu, Shoudeng Chen, David C. Chan, Junjie Hu & Song Gao
Abstract
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.
文章链接：https://www.nature.com/articles/s41467-019-12912-0