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MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion

Cao, Yu-Lu and Meng, Shuxia and Chen, Yang and Feng, Jian-Xiong and Gu, Dong-Dong and Yu, Bing and Li, Yu-Jie and Yang, Jin-Yu and Liao, Shuang and Chan, David C. and Gao, Song (2017) MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. Nature, 542 (7641). pp. 372-376. ISSN 0028-0836. PMCID PMC5319402. https://resolver.caltech.edu/CaltechAUTHORS:20161216-173743897

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[img] Image (JPEG) (Extended Data Figure 1: MFN1 constructs and their biochemical properties) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 2: Overall structure of MFN1_(IM)) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 3: Sequence alignment of mitofusins and BDLP) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 4: Structural comparison of MFN1_(IM) with other dynamin family members) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 5: Structural comparison of MFN1_(IM) with BDLP and dynamin-1) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 6: Dimerization of MFN1_(IM) G domains in the transition-like state) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 7: Analysis of the switch I conformations) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 8: Characterization of MFN1_(ΔTM) and the Asp189 trigger) - Supplemental Material
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[img] Image (JPEG) (Extended Data Figure 9: Proposed model for MFN1-mediated OMM fusion) - Supplemental Material
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Abstract

Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli. Their dynamic morphology is a result of regulated and balanced fusion and fission processes. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential. Mitofusins are dynamin-related GTPases that are essential for mitochondrial fusion. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via combined oligomerization and GTP hydrolysis. However, the molecular mechanisms of this process remain unknown. Here we present crystal structures of engineered human MFN1 containing the GTPase domain and a helical domain during different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of MFN1 and resembles the ‘neck’ of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote GTPase domain dimerization in the transition state. Disruption of GTPase domain dimerization abolishes the fusogenic activity of MFN1. Moreover, a conserved aspartate residue trigger was found to affect mitochondrial elongation in MFN1, probably through a GTP-loading-dependent domain rearrangement. Thus, we propose a mechanistic model for MFN1-mediated mitochondrial tethering, and our results shed light on the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/nature21077DOIArticle
http://www.nature.com/nature/journal/v542/n7641/full/nature21077.htmlPublisherArticle
http://rdcu.be/oOzKPublisherFree ReadCube access
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319402/PubMed CentralArticle
Alternate Title:Crystal structure of Mitofusin 1 reveals nucleotide-triggered dimerization critical for mitochondrial fusion
Additional Information:© 2017 Macmillan Publishers Limited. Received 27 July 2016; accepted 3 January 2017. Published online 23 January 2017. We thank the staff at beamline BL17U1 of SSRF for the help with the collection of diffraction data, W.-L. Huang and H.-Y. Wang for technical assistance, J. Hu and X. Guo for advice on liposome tethering assay, and O. Daumke for comments on the manuscript. This work was supported by grants of National Basic Research Program of China (2013CB910500), National Natural Science Foundation of China (31200553), Natural Science Foundation of Guangdong Province (2014TQ01R584 and 2014A030312015), New Century Excellent Talents in University (NCET-12-0567) and the Recruitment Program of Global Youth Experts to S.G., and the National Institutes of Health (GM110039 and GM119388) to D.C.C. Data availability: The X-ray crystallographic coordinates and structure factor files for MFN1IM structures have been deposited in the Protein Data Bank (PDB) under the following accession numbers: 5GO4 (apo MFNIMB), 5GOF (GTP-bound MFN1IMC(T109A)), 5GOM (transition-like state MFN1IMC), and 5GOE (GDP-bound MFN1IMC(T109A)). All other data generated or analysed during this study are included in this published article, and are available from the corresponding author upon reasonable request. Author Contributions: S.G. and D.C.C. conceived the project. Y.-L.C. made the constructs, purified proteins, and performed crystallographic and biochemical experiments. S.M. carried out mitochondrial elongation assays. Y.C. performed ITC measurements and helped with collection of X-ray diffraction data. J.-X.F., B.Y. and Y.-J.L. performed cloning and purification for some of the MFN1IM mutants. D.-D.G. performed some of the SEC-RALS experiments, D.-D.G., J.-Y.Y. and S.L. helped with crystallization experiments. Y.-L.C., S.L. and S.G. solved the structures. Y.-L.C., D.C.C. and S.G. wrote the paper. The authors declare no competing financial interests. Reviewer Information: Nature thanks M. Ford and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Funders:
Funding AgencyGrant Number
National Basic Research Program of China2013CB910500
National Natural Science Foundation of China31200553
Natural Science Foundation of Guangdong Province 2014TQ01R584
Natural Science Foundation of Guangdong Province 2014A030312015
New Century Excellent Talents in UniversityNCET-12-0567
Recruitment Program of Global Youth ExpertsUNSPECIFIED
NIHGM110039
NIHGM119388
Issue or Number:7641
PubMed Central ID:PMC5319402
Record Number:CaltechAUTHORS:20161216-173743897
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20161216-173743897
Official Citation:MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion Yu-Lu Cao, Shuxia Meng, Yang Chen, Jian-Xiong Feng, Dong-Dong Gu, Bing Yu, Yu-Jie Li, Jin-Yu Yang, Shuang Liao, David C. Chan & Song Gao Nature 542, 372–376 (16 February 2017) doi:10.1038/nature21077
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:72921
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:26 Jan 2017 21:18
Last Modified:03 Oct 2019 16:22

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