ACIDIC BICELLES ARE A SUITABLE MEMBRANE MIMIC FOR STRUCTURAL STUDIES OF THE LASSA VIRUS FUSION DOMAIN.

Pennington, H. N.; Lee, J.

doi:10.1101/2025.03.11.642635

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bioRxiv · 10.1101/2025.03.11.642635

ACIDIC BICELLES ARE A SUITABLE MEMBRANE MIMIC FOR STRUCTURAL STUDIES OF THE LASSA VIRUS FUSION DOMAIN.

Pennington, H. N.·Lee, J.

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Abstract

AO_SCPLOWBSTRACTC_SCPLOWLassa virus (LASV) is the most prevalent arenavirus afflicting humans and has high pandemic potential. The genetic material of LASV is delivered into the host cell via membrane fusion - a process initiated by the LASV fusion domain (FD). However, the molecular details of the LASV FD, particularly its structure after association with the host cell, remain poorly understood. This can be attributed to a lack of a viable membrane mimic to effectively stabilize the LASV FD for structural studies. Here, we demonstrate that the structure of the LASV FD widely varies based on the class of membrane mimic. In particular, through CD spectroscopy, we found that the LASV FD required a charged membrane mimic, such as zwitterionic or anionic detergent micelles, to adopt a helical conformation at low pH, but has the highest helical content in the presence of anionic lipids, particularly the detergent micelle LMPG and acidic bicelles. Moreover, we reveal that the LASV FD was well resolved on NMR spectra in CHAPS, DPC, LDAO, LMPG, and acidic bicelles, where LMPG and acidic bicelles had the sharpest peak resolution, but more defined peaks were noted in acidic bicelles over LMPG. In conclusion, our findings indicate that acidic bicelles are the optimal membrane mimic for the stabilization of the LASV FD such that structural studies can be conducted. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/642635v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@7e8dfcorg.highwire.dtl.DTLVardef@9bb650org.highwire.dtl.DTLVardef@de6fbdorg.highwire.dtl.DTLVardef@179e8eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Pennington, H. N., Lee, J.. 2025-03-12. ACIDIC BICELLES ARE A SUITABLE MEMBRANE MIMIC FOR STRUCTURAL STUDIES OF THE LASSA VIRUS FUSION DOMAIN.. https://doi.org/10.1101/2025.03.11.642635

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