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Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites

Author

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  • Eugenio Mora

    (PSL Research University, CNRS UMR168
    Sorbonne Université)

  • Manuela Dezi

    (PSL Research University, CNRS UMR168
    Sorbonne Université)

  • Aurélie Cicco

    (PSL Research University, CNRS UMR168
    Sorbonne Université)

  • Joëlle Bigay

    (CNRS UMR 7275, Université Côte d’Azur, Institut de Pharmacologie Moléculaire et Cellulaire)

  • Romain Gautier

    (CNRS UMR 7275, Université Côte d’Azur, Institut de Pharmacologie Moléculaire et Cellulaire)

  • John Manzi

    (PSL Research University, CNRS UMR168
    Sorbonne Université)

  • Joël Polidori

    (CNRS UMR 7275, Université Côte d’Azur, Institut de Pharmacologie Moléculaire et Cellulaire)

  • Daniel Castaño-Díez

    (University of Basel)

  • Bruno Mesmin

    (CNRS UMR 7275, Université Côte d’Azur, Institut de Pharmacologie Moléculaire et Cellulaire)

  • Bruno Antonny

    (CNRS UMR 7275, Université Côte d’Azur, Institut de Pharmacologie Moléculaire et Cellulaire)

  • Daniel Lévy

    (PSL Research University, CNRS UMR168
    Sorbonne Université)

Abstract

Membrane contact sites (MCS) are subcellular regions where two organelles appose their membranes to exchange small molecules, including lipids. Structural information on how proteins form MCS is scarce. We designed an in vitro MCS with two membranes and a pair of tethering proteins suitable for cryo-tomography analysis. It includes VAP-A, an ER transmembrane protein interacting with a myriad of cytosolic proteins, and oxysterol-binding protein (OSBP), a lipid transfer protein that transports cholesterol from the ER to the trans Golgi network. We show that VAP-A is a highly flexible protein, allowing formation of MCS of variable intermembrane distance. The tethering part of OSBP contains a central, dimeric, and helical T-shape region. We propose that the molecular flexibility of VAP-A enables the recruitment of partners of different sizes within MCS of adjustable thickness, whereas the T geometry of the OSBP dimer facilitates the movement of the two lipid-transfer domains between membranes.

Suggested Citation

  • Eugenio Mora & Manuela Dezi & Aurélie Cicco & Joëlle Bigay & Romain Gautier & John Manzi & Joël Polidori & Daniel Castaño-Díez & Bruno Mesmin & Bruno Antonny & Daniel Lévy, 2021. "Nanoscale architecture of a VAP-A-OSBP tethering complex at membrane contact sites," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23799-1
    DOI: 10.1038/s41467-021-23799-1
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    Cited by:

    1. Bao-cun Zhang & Marlene F. Laursen & Lili Hu & Hossein Hazrati & Ryo Narita & Lea S. Jensen & Aida S. Hansen & Jinrong Huang & Yan Zhang & Xiangning Ding & Maimaitili Muyesier & Emil Nilsson & Agniesz, 2024. "Cholesterol-binding motifs in STING that control endoplasmic reticulum retention mediate anti-tumoral activity of cholesterol-lowering compounds," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Wenbin Zhong & Weize Lin & Yingjie Yang & Dan Chen & Xiuye Cao & Mengyang Xu & Guoping Pan & Huanzhao Chen & Jie Zheng & Xiaoqin Feng & Li hua Yang & Chaofeng Lai & Vesa M. Olkkonen & Jun Xu & Shuzhon, 2022. "An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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