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

By Eugenio De la Mora Lugo, Manuela Dezi, Aurelie Di Cicco, Joelle Bigay, Romain Gautier, John Manzi, Daniel Castano Diez, Bruno Mesmin, Bruno Antonny, Daniel Levy

Posted 13 Oct 2020
bioRxiv DOI: 10.1101/2020.10.13.337493

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. ### Competing Interest Statement The authors have declared no competing interest.

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