The process of membrane fusion: Nipples, hemifusion, pores, and pore growth

Abstract

In this chapter we discuss the current understanding of the process of membrane fusion and the contributions of proteins and lipids to this process. Many viral fusion proteins and proteins probably responsible for intracellular fusion fold into a bundle of coiled-coils. Formation of these coiled-coils is thought to be responsible for bringing membranes close together and may also cause the fusion event. Based on studies using the hemagglutinin (HA) of influenza virus, a prototypic fusion protein, the most likely sequence for fusion is as follows: Membranes make local contact by bending toward each other; the contacting lipid monolayers merge at these sites, yielding a state of hemifusion; with the subsequent merger of distal leaflets, fusion is completed. Many properties of lipids contribute to the fusion process. Important among these is spontaneous monolayer curvature. The contribution of spontaneous curvature to fusion is the best-understood aspect of the process in quantitative biophysical terms. Positive spontaneous curvature of contacting leaflets inhibits hemifusion, negative spontaneous curvature promotes it. Intermediate states that exhibit properties of hemifusion and can proceed on to full fusion have been captured and characterized. The transmembrane domain of HA greatly augments the transition from hemifusion to full fusion, but is not essential. The amino acid sequence of this domain is not critical, indicating that the conversion of hemifused to fused membranes occurs by a physical process. The growth of fusion pores is regulated by fusion proteins and affected by the lipid composition of the fused membranes.