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

Li, Yu-Jie and Cao, Yu-Lu and Feng, Jian-Xiong and Qi, Yuanbo and Meng, Shuxia and Yang, Jie-Feng and Zhong, Ya-Ting and Kang, Sisi and Chen, Xiaoxue and Lan, Lan and Luo, Li and Yu, Bing and Chen, Shoudeng and Chan, David C. and Hu, Junjie and Gao, Song (2019) Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset. Nature Communications, 10 . Art. No. 4914. ISSN 2041-1723. PMCID PMC6820788.

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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.

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URLURL TypeDescription CentralArticle
Li, Yu-Jie0000-0002-8425-386X
Cao, Yu-Lu0000-0002-5239-1184
Qi, Yuanbo0000-0002-6589-3677
Chan, David C.0000-0002-0191-2154
Hu, Junjie0000-0003-4712-2243
Gao, Song0000-0001-7427-6681
Additional Information:© 2019 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit Received 02 April 2019; Accepted 02 October 2019; Published 29 October 2019. Data availability: Data supporting the findings of this paper are available from the corresponding author upon reasonable request. A reporting summary for this article is available as a Supplementary Information file. The source data underlying Figs. 2a, d, 4h, 5b–f, 6b, a and Supplementary Figs. 3e, 4a, 5f, 6e, f, 7b, c are provided as a Source Data file. The X-ray crystallographic coordinates and structure factor files for MFN2IM structures have been deposited in the Protein Data Bank (PDB) under the following accession numbers: 6JFL for nucleotide-free MFN2IM, 6JFK for GDP-bound MFN2IM, and 6JFM for MFN2IM(T111D). We thank the staff of SSRF for the help with the collection of crystal diffraction data, Prof Tengchuan Jin for sharing the MBP plasmids, and Prof Oliver Daumke for the comments on the paper. This work was supported by following grants: National Key R&D Program of China to S.G. (2018YFA0508300), National Natural Science Foundation of China to S.G. (31722016, 31470729, and 81772977) and to Y.-L.C. (81802730), Natural Science Foundation of Guangdong Province to S.G. (2014TQ01R584 and 2014A030312015), Innovative Team Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory to S.G. (2018GZR110103002), the National Institutes of Health to D.C.C. (GM110039 and GM119388). Author Contributions: S.G. and Y.-L.C. conceived the project. Y,-J.L, and Y.-L.C. made the constructs, and solved structures. Y,-J.L. and J.-X.F. purified proteins, performed crystallographic, and most of the biochemical experiments. Y.Q. and L.L. carried out analytical ultracentrifugation and FRET experiments. S.M. did mitochondrial elongation assays. J.-F.Y. did native PAGE experiments, Y.-T.Z., L.L., S.K., X.C. and B.Y. helped with protein purification and biochemical experiments. S.C., Y.-L.C., J.H, D.C.C. and S.G. analyzed data. S.G. wrote the paper. The authors declare no competing interests.
Funding AgencyGrant Number
National Key Research and Development Program of China2018YFA0508300
National Natural Science Foundation of China31722016
National Natural Science Foundation of China31470729
National Natural Science Foundation of China81772977
National Natural Science Foundation of China81802730
Natural Science Foundation of Guangdong Province2014TQ01R584
Natural Science Foundation of Guangdong Province2014A030312015
Guangzhou Regenerative Medicine and Health Guangdong Laboratory2018GZR110103002
Subject Keywords:Enzyme mechanisms; Mitochondria; Neurodegenerative diseases; X-ray crystallography
PubMed Central ID:PMC6820788
Record Number:CaltechAUTHORS:20191105-105608947
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Official Citation:Li, Y., Cao, Y., Feng, J. et al. Structural insights of human mitofusin-2 into mitochondrial fusion and CMT2A onset. Nat Commun 10, 4914 (2019) doi:10.1038/s41467-019-12912-0
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:99676
Deposited By: Tony Diaz
Deposited On:05 Nov 2019 19:32
Last Modified:05 Nov 2019 19:32

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