Cholesterol-Mediated Clustering of the HIV Fusion Protein gp41 in Lipid Bilayers
Name
nihms-1775288.pdf
Description
Accepted version
Size
1.82 MB
Format
Adobe PDF
Checksum (MD5)
80bd1f2a2dfc16a5ca804e702ef682b1
Author(s)
Tran, Nhi
Oh, Younghoon
Sutherland, Madeleine
Cui, Qiang
Hong, Mei
Date Issued
January 30, 2022
Journal
Journal of Molecular Biology
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
The envelope glycoprotein (Env) of the human immunodeficient virus (HIV-1) is known to cluster on the viral membrane surface to attach to target cells and cause membrane fusion for HIV-1 infection. However, the molecular structural mechanisms that drive Env clustering remain opaque. Here, we use solid-state NMR spectroscopy and molecular dynamics (MD) simulations to investigate nanometer-scale clustering of the membrane-proximal external region (MPER) and transmembrane domain (TMD) of gp41, the fusion protein component of Env. Using 19F solid-state NMR experiments of mixed fluorinated peptides, we show that MPER-TMD trimers form clusters with interdigitated MPER helices in cholesterol-containing membranes. Inter-trimer 19F-19F cross peaks, which are indicative of spatial contacts within ∼2 nm, are observed in cholesterol-rich virus-mimetic membranes but are suppressed in cholesterol-free model membranes. Water-peptide and lipid-peptide cross peaks in 2D 1H-19F correlation spectra indicate that the MPER is well embedded in model phosphocholine membranes but is more exposed to the surface of the virus-mimetic membrane. These experimental results are reproduced in coarse-grained and atomistic molecular dynamics simulations, which suggest that the effects of cholesterol on gp41 clustering is likely via indirect modulation of the MPER orientation. Cholesterol binding to the helix-turn-helix region of the MPER-TMD causes a parallel orientation of the MPER with the membrane surface, thus allowing MPERs of neighboring trimers to interact with each other to cause clustering. These solid-state NMR data and molecular dynamics simulations suggest that MPER and cholesterol cooperatively govern the clustering of gp41 trimers during virus-cell membrane fusion.
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Creative Commons Attribution-NonCommercial-NoDerivatives
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DOI of Published Version
https://doi.org/10.1016/j.jmb.2021.167345
