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      Bis(Monoacylglycero)Phosphate Promotes Membrane Fusion Facilitated by the SARS-CoV-2 Fusion Domain.

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          Abstract

          Membrane fusion is a critical component of the viral lifecycle. For SARS-CoV-2, fusion is facilitated by the spike glycoprotein and can take place via either the plasma membrane or the endocytic pathway. The fusion domain (FD), which is found within the spike glycoprotein, is primarily responsible for the initiation of fusion as it embeds itself within the target cell's membrane. A preference for SARS-CoV-2 to fuse at low pH akin to the environment of the endocytic pathway has already been established; however, the impact of the target cell's lipid composition on the FD has yet to be explored. Here, we have shown that the SARS-CoV-2 FD preferentially initiates fusion at the late endosomal membrane over the plasma membrane, on the basis of lipid composition alone. A positive, fusogenic relationship with anionic lipids from the plasma membrane (POPS: 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-l-serine) and endosomal membrane (BMP: bis(monoacylglycero)phosphate) was established, with a large preference demonstrated for the latter. When comparing the binding affinity and secondary structure of the FD in the presence of different anionic lipids, little deviation was evident while the charge was maintained. However, it was discovered that BMP had a subtle, negative impact on lipid packing in comparison to that of POPS. Furthermore, an inverse relationship between lipid packing and the fusogenecity of the SARS-CoV-2 FD was witnessed. In conclusion, the SARS-CoV-2 FD preferentially initiates fusion at a membrane resembling that of the late endosomal compartment, predominately due to the presence of BMP and its impact on lipid packing.

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          Author and article information

          Journal
          J Phys Chem B
          The journal of physical chemistry. B
          American Chemical Society (ACS)
          1520-5207
          1520-5207
          Mar 21 2024
          : 128
          : 11
          Affiliations
          [1 ] Department of Chemistry and Biochemistry, University of Maryland, College Park 20742, Maryland, United States.
          Article
          10.1021/acs.jpcb.3c07863
          38466655
          b985e6e0-1284-4998-aec3-e500c247d42b
          History

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