Abstract
Lipid-conjugated peptides have advanced the understanding of membrane protein functions and the roles of lipids in the membrane milieu. These lipopeptides modulate various biological systems such as viral fusion. A single function has been suggested for the lipid, binding to the membrane and thus elevating the local concentration of the peptide at the target site. In the present paper, we challenged this argument by exploring in-depth the antiviral mechanism of lipopeptides, which comprise sphinganine, the lipid backbone of DHSM (dihydrosphingomyelin), and an HIV-1 envelope-derived peptide. Surprisingly, we discovered a partnership between the lipid and the peptide that impaired early membrane fusion events by reducing CD4 receptor lateral diffusion and HIV-1 fusion peptide-mediated lipid mixing. Moreover, only the joint function of sphinganine and its conjugate peptide disrupted HIV-1 fusion protein assembly and folding at the later fusion steps. Via imaging techniques we revealed for the first time the direct localization of these lipopeptides to the virus–cell and cell–cell contact sites. Overall, the findings of the present study may suggest lipid–protein interactions in various biological systems and may help uncover a role for elevated DHSM in HIV-1 and its target cell membranes.
Highlights
HIV-1 entry into the cells is blocked by alteration in the levels of Chol and sphingolipids that are essential structural components of the cell membrane [1,2]
A gp41-central coiled-coil is formed from a trimer of NHR (N-heptad repeat) regions packed into three C-heptad repeat (CHR) (Cheptad repeat) regions
Various peptides derived from membrane proteins have been conjugated to lipids to exert diverse effects on biological systems within the membrane milieu [25,33,34]
Summary
HIV-1 entry into the cells is blocked by alteration in the levels of Chol (cholesterol) and sphingolipids that are essential structural components of the cell membrane [1,2]. Sphingolipids and Chol form assemblies in the cell membrane termed ordered domains [3], which mediate virion release from the cells and entry into them [4,5,6]. A gp41-central coiled-coil is formed from a trimer of NHR (N-heptad repeat) regions packed into three CHR (Cheptad repeat) regions. This core structure, termed the SHB (six helix bundle) is important for complete membrane fusion and pore formation [13,14,15,16]. Disruption of the core formation is an established target for N- and C-peptide fusion inhibitors, which are derived from the NHR and CHR regions respectively [16,17,18,19,20]
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