Abstract
Lipids and proteins are organized in cellular membranes in clusters, often called ‘lipid rafts'. Although raft-constituent ordered lipid domains are thought to be energetically unfavourable for membrane fusion, rafts have long been implicated in many biological fusion processes. For the case of HIV gp41-mediated membrane fusion, this apparent contradiction can be resolved by recognizing that the interfaces between ordered and disordered lipid domains are the predominant sites of fusion. Here we show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. Line-active compounds such as vitamin E lower line tension in inhomogeneous membranes, thereby inhibit membrane fusion, and thus may be useful natural viral entry inhibitors.
Highlights
Lipids and proteins are organized in cellular membranes in clusters, often called ‘lipid rafts’
To shed light on the mechanism of membrane fusion at lipid phase boundaries, we explore in the current work the effect of hydrophobic mismatch between Lo- and Ld-domain thickness, the effect of different sterols and the effect of a series of ‘linactants’ on Human immunodeficiency virus (HIV) fusion peptide (HIV-FP)-mediated membrane fusion (Fig. 1)
Our studies show that line tension is the common denominator that determines the energetics of HIV gp41-fusion peptide insertion into the target membrane and subsequent membrane fusion
Summary
Lipids and proteins are organized in cellular membranes in clusters, often called ‘lipid rafts’. We show that line tension at lipid domain boundaries contributes significant energy to drive gp41-fusion peptide-mediated fusion. This energy, which depends on the hydrophobic mismatch between ordered and disordered lipid domains, may contribute tens of kBT to fusion, that is, it is comparable to the energy required to form a lipid stalk intermediate. To shed light on the mechanism of membrane fusion at lipid phase boundaries, we explore in the current work the effect of hydrophobic mismatch between Lo- and Ld-domain thickness, the effect of different sterols and the effect of a series of ‘linactants’ on HIV fusion peptide (HIV-FP)-mediated membrane fusion (Fig. 1). (i) Changing components of raft-like Lo domains (ii) Modifying hydrophobic mismatch between Lo and Ld phases (iii) Introducing ‘linactants’
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