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Structural basis of mitochondrial receptor binding and constriction by DRP1

Author

Listed:
  • Raghav Kalia

    (University of California, San Francisco
    University of Utah
    California Institute for Quantitative Biomedical Research)

  • Ray Yu-Ruei Wang

    (University of California, San Francisco
    California Institute for Quantitative Biomedical Research
    Howard Hughes Medical Institute)

  • Ali Yusuf

    (University of California, San Francisco
    California Institute for Quantitative Biomedical Research)

  • Paul V. Thomas

    (University of California, San Francisco
    California Institute for Quantitative Biomedical Research)

  • David A. Agard

    (University of California, San Francisco
    California Institute for Quantitative Biomedical Research
    Howard Hughes Medical Institute)

  • Janet M. Shaw

    (University of Utah
    Howard Hughes Medical Institute)

  • Adam Frost

    (University of California, San Francisco
    University of Utah
    California Institute for Quantitative Biomedical Research
    Chan Zuckerberg Biohub)

Abstract

Mitochondrial inheritance, genome maintenance and metabolic adaptation depend on organelle fission by dynamin-related protein 1 (DRP1) and its mitochondrial receptors. DRP1 receptors include the paralogues mitochondrial dynamics proteins of 49 and 51 kDa (MID49 and MID51) and mitochondrial fission factor (MFF); however, the mechanisms by which these proteins recruit and regulate DRP1 are unknown. Here we present a cryo-electron microscopy structure of full-length human DRP1 co-assembled with MID49 and an analysis of structure- and disease-based mutations. We report that GTP induces a marked elongation and rotation of the GTPase domain, bundle-signalling element and connecting hinge loops of DRP1. In this conformation, a network of multivalent interactions promotes the polymerization of a linear DRP1 filament with MID49 or MID51. After co-assembly, GTP hydrolysis and exchange lead to MID receptor dissociation, filament shortening and curling of DRP1 oligomers into constricted and closed rings. Together, these views of full-length, receptor- and nucleotide-bound conformations reveal how DRP1 performs mechanical work through nucleotide-driven allostery.

Suggested Citation

  • Raghav Kalia & Ray Yu-Ruei Wang & Ali Yusuf & Paul V. Thomas & David A. Agard & Janet M. Shaw & Adam Frost, 2018. "Structural basis of mitochondrial receptor binding and constriction by DRP1," Nature, Nature, vol. 558(7710), pages 401-405, June.
    • Handle: RePEc:nat:nature:v:558:y:2018:i:7710:d:10.1038_s41586-018-0211-2
    DOI: 10.1038/s41586-018-0211-2
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    Cited by:

    1. Chih-Wei Chen & Chi Su & Chang-Yu Huang & Xuan-Rong Huang & Xiaojing Cuili & Tung Chao & Chun-Hsiang Fan & Cheng-Wei Ting & Yi-Wei Tsai & Kai-Chien Yang & Ti-Yen Yeh & Sung-Tsang Hsieh & Yi-Ju Chen & , 2024. "NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Donghua Hu & Min Tan & Dongliang Lu & Brian Kleiboeker & Xuejing Liu & Hongsuk Park & Alexxai V. Kravitz & Kooresh I. Shoghi & Yu-Hua Tseng & Babak Razani & Akihiro Ikeda & Irfan J. Lodhi, 2023. "TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    3. Lucas Gewehr & Benedikt Junglas & Ruven Jilly & Johannes Franz & Wenyu Eva Zhu & Tobias Weidner & Mischa Bonn & Carsten Sachse & Dirk Schneider, 2023. "SynDLP is a dynamin-like protein of Synechocystis sp. PCC 6803 with eukaryotic features," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Isabel Pérez-Jover & Kristy Rochon & Di Hu & Mukesh Mahajan & Pooja Madan Mohan & Isaac Santos-Pérez & Julene Ormaetxea Gisasola & Juan Manuel Martinez Galvez & Jon Agirre & Xin Qi & Jason A. Mears & , 2024. "Allosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    6. Huan Yang & Caroline Sibilla & Raymond Liu & Jina Yun & Bruce A. Hay & Craig Blackstone & David C. Chan & Robert J. Harvey & Ming Guo, 2022. "Clueless/CLUH regulates mitochondrial fission by promoting recruitment of Drp1 to mitochondria," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    7. Luis Rios & Suman Pokhrel & Sin-Jin Li & Gwangbeom Heo & Bereketeab Haileselassie & Daria Mochly-Rosen, 2023. "Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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