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May 22nd, 2025
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University of Maryland College Park
biochemistry
biorxiv

THE LASSA VIRUS FUSION DOMAIN HAS STRUCTURAL PLASTICITY AND EXPLOITS BIS(MONOACYLGLYCERO)PHOSPHATE FOR FUSION

Pennington, H. N.Open in Google Scholar•Arulmoly, K.Open in Google Scholar•Mulvihill, Q. M.Open in Google Scholar•Shin, S.Open in Google Scholar•Im, W.Open in Google Scholar•Lee, J.Open in Google Scholar

Infection with Lassa virus (LASV), an arenavirus endemic to West Africa, results in a viral hemorrhagic fever with high mortality rates and public health implications. The glycoprotein complex (GPC) is central to LASV\'s infectivity as it mediates viral entry via membrane fusion. The fusion domain (FD, G260 - N295) facilitates the initiation of membrane fusion and, thus, the merging of the viral and host cell membranes in a pH-dependent fashion at the lysosomal membrane. The FD consists of two distinct regions: an N-terminal fusion peptide (FP, G260 - T274) and an internal fusion loop (FL, C279 - N295) that are connected by a short linker region (P275 - Y278). Nonetheless, the precise structural and functional characteristics of the LASV FD remain unknown. Here, we demonstrate that the LASV FD associates with the host cell membrane via its FL, specifically residues R282 - L290, whereas the FP is more solvent-exposed, especially for residues D268 - T274. We found that a multitude of conformational states are adopted by the entire LASV FD before membrane association, while only the FP, and not the FL, continues to sample numerous states after membrane association. Moreover, we provide evidence that the LASV FD prefers to interact with anionic lipids, namely bis(monoacylglycero)phosphate (BMP). In conclusion, our findings indicate that the LASV FD preferentially initiates fusion in the presence of BMP, at which point the FL adopts a helical conformation to associate with the membrane, whereas the FP remains exposed to the environment.

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