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

Eugenio Mora, Manuela Dezi (), Aurélie Cicco, Joëlle Bigay, Romain Gautier, John Manzi, Joël Polidori, Daniel Castaño-Díez, Bruno Mesmin, Bruno Antonny () and Daniel Lévy ()
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Eugenio Mora: PSL Research University, CNRS UMR168
Manuela Dezi: PSL Research University, CNRS UMR168
Aurélie Cicco: PSL Research University, CNRS UMR168
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23799-1

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