Mechanisms of enveloped virus entry by membrane fusion

Viruses initiate infection by transferring their nucleocapsids into the cytosol. Nucleocapsids of enveloped viruses are surrounded by a lipid bilayer membrane (hence the term ‘enveloped’) derived from the host cell (Figure 1). Thus, in order to deliver their genetic material into target cells, enveloped viruses must merge their membrane with a cell membrane. Membrane merger is an energy-intensive process that does not usually occur without the help of specialized proteins. Enveloped viruses encode integral membrane glycoproteins, referred to as fusion proteins, which are responsible for binding to cellular receptors and mediating membrane fusion. When triggered by proper stimuli in the form of a cellular receptor(s) and/or acidic pH in endosomes, these proteins undergo dramatic conformational changes, resulting in the merger of viral and target membranes. The widely held view of viral fusogens is that these proteins are trapped in a meta-stable ‘spring-loaded’ conformation that can promote membrane fusion as it releases the stored energy and refolds into a more stable structure. Progress in understanding the mechanism of viral fusion has been slow due to difficulties in crystallizing membrane proteins, further confounded by the intrinsic propensity of viral fusogens to undergo conformational changes. Despite these problems, fragments of many viral fusogens have been crystallized and their structures solved.^1–8 These advances in structural characterization of viral fusogens revealed a dazzling variability of their amino acid sequences and structures. Distinctly different architectures of these proteins, along with varying placement of conserved domains, led to their current categorization into three classes (see Section....