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    Ebola virus glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry

    Year: 2021

    Journal: Nat. Struct. Mol. Biol., Volume 28, FEB, page 181

    Authors: Lee, Jinwoo; Kreutzberger, Alex J. B.; Odongo, Laura; Nelson, Elizabeth A.; Nyenhuis, David A.; Kiessling, Volker; Liang, Binyong; Cafiso, David S.; White, Judith M.; Tamm, Lukas K.

    Organizations: NIH [R01 AI030557, R01 AI114776, T32 GM080186]; Human Frontiers Science Program [RGP0055/2015]

    Cholesterol serves critical roles in enveloped virus fusion by modulating membrane properties. The glycoprotein (GP) of Ebola virus (EBOV) promotes fusion in the endosome, a process that requires the endosomal cholesterol transporter NPC1. However, the role of cholesterol in EBOV fusion is unclear. Here we show that cholesterol in GP-containing membranes enhances fusion and the membrane-proximal external region and transmembrane (MPER/TM) domain of GP interacts with cholesterol via several glycine residues in the GP2 TM domain, notably G660. Compared to wild-type (WT) counterparts, a G660L mutation caused a more open angle between MPER and TM domains in an MPER/TM construct, higher probability of stalling at hemifusion for GP2 proteoliposomes and lower cell entry of virus-like particles (VLPs). VLPs with depleted cholesterol show reduced cell entry, and VLPs produced under cholesterol-lowering statin conditions show less frequent entry than respective controls. We propose that cholesterol-TM interactions affect structural features of GP2, thereby facilitating fusion and cell entry.
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