The envelope glycoprotein gp41 mediates the process of membrane fusion which enables entry of the HIV-1 virus into the host cell. Strong lipid affinity of the ectodomain suggests that its heptad repeat regions play an active role in destabilizing membranes by directly binding to the lipid bilayers and thereby lowering the free-energy barrier for membrane fusion. In such a model, immediately following the shedding of gp120, the N-heptad and C-heptad helices dissociate and melt into the host cell and viral membranes, respectively, pulling the destabilized membranes into juxtaposition, ready for fusion. Post-fusion, reaching the final 6-helix bundle (6HB) conformation then involves competition between intermolecular interactions needed for formation of the symmetric 6HB trimer and the membrane affinity of gp41's ectodomain, including its membrane-proximal regions. Our solution NMR study and frozen pulsed EPR studies of the structural and dynamic properties of multiple constructs containing the ectodomain of gp41 with and without its membrane-proximal regions suggests that these segments do not form inter-helical interactions until the very late steps of the fusion process but are critical for formation of the 6HB. Remarkably, the transmembrane anchoring domain, studied in mixed micelles (bicelles) by residual dipolar couplings, pulsed EPR, paramagnetic relaxation, and other analytical techniques deviates pronouncedly from the widely accepted structural model.

NMR study of the pre-fusion to post-fusion transition of the gp41 ecto domain

254th National Meeting (2017)

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