Many viruses are enveloped by a membrane taken during budding from an infected host cell. An early step in infection of a new cell is joining (fusion) of the viral and host membranes, and is mediated by a fusion protein in the viral membrane. Initial contact with the host membrane is made by a ~25-residue “fusion peptide” segment. We hypothesize that the fusion peptide locally modifies the host membrane which reduces the activation barrier for fusion. We are therefore developing a solid-state NMR approach to probe specific protein/lipid contacts via protein 13C-to-lipid 31P or 2H rotational-echo double-resonance (REDOR). Protein/lipid geometries are determined using our approach, as well as the populations of the different contact geometries adopted by the protein. In addition, protein preferences are determined for contact with specific lipids, as well as the relative energies of contacts with these different lipids. Our application of this approach to lipid contacts of fusion peptides from influenza virus and from human immunodeficiency virus evidence unusual membrane topologies. These topologies are consistent with lipid configurations different from a typical bilayer and more like those in fusion intermediates. Our data also demonstrate fusion peptide preference for contact with cholesterol, which supports the "cholesterol as fusogen" hypothesis.

Solid-state NMR of protein/lipid contacts of viral fusion peptides

254th National Meeting (2017)

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