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Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites

Author

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  • Hyunwoo Kim

    (Ulsan National Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Seowhang Lee

    (Ulsan National Institute of Science and Technology)

  • Youngsoo Jun

    (Gwangju Institute of Science and Technology
    Gwangju Institute of Science and Technology)

  • Changwook Lee

    (Ulsan National Institute of Science and Technology
    Gwangju Institute of Science and Technology)

Abstract

The endoplasmic reticulum (ER)-mitochondria contact site (ERMCS) is crucial for exchanging biological molecules such as phospholipids and Ca2+ ions between these organelles. Mitoguardin-2 (MIGA2), a mitochondrial outer membrane protein, forms the ERMCS in higher eukaryotic cells. Here, we report the crystal structures of the MIGA2 Lipid Droplet (LD) targeting domain and the ER membrane protein VAPB bound to the phosphorylated FFAT motif of MIGA2. These structures reveal that the MIGA2 LD targeting domain has a large internal hydrophobic pocket that accommodates phospholipids and that two phosphorylations of the FFAT motif are required for tight interaction of MIGA2 with VAPB, which enhances the rate of lipid transport. Further biochemical studies show that MIGA2 transports phospholipids between membranes with a strong preference for binding and trafficking phosphatidylserine (PS). These results provide a structural and molecular basis for understanding how MIGA2 mediates the formation of ERMCS and facilitates lipid trafficking at the ERMCS.

Suggested Citation

  • Hyunwoo Kim & Seowhang Lee & Youngsoo Jun & Changwook Lee, 2022. "Structural basis for mitoguardin-2 mediated lipid transport at ER-mitochondrial membrane contact sites," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31462-6
    DOI: 10.1038/s41467-022-31462-6
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    References listed on IDEAS

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    1. Kenji Maeda & Kanchan Anand & Antonella Chiapparino & Arun Kumar & Mattia Poletto & Marko Kaksonen & Anne-Claude Gavin, 2013. "Interactome map uncovers phosphatidylserine transport by oxysterol-binding proteins," Nature, Nature, vol. 501(7466), pages 257-261, September.
    2. Yasunori Watanabe & Yasushi Tamura & Shin Kawano & Toshiya Endo, 2015. "Structural and mechanistic insights into phospholipid transfer by Ups1–Mdm35 in mitochondria," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    3. Radu Stoica & Kurt J. De Vos & Sébastien Paillusson & Sarah Mueller & Rosa M. Sancho & Kwok-Fai Lau & Gema Vizcay-Barrena & Wen-Lang Lin & Ya-Fei Xu & Jada Lewis & Dennis W. Dickson & Leonard Petrucel, 2014. "ER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43," Nature Communications, Nature, vol. 5(1), pages 1-12, September.
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