Cell entry of enveloped viruses

Abstract

Infection of cells by enveloped viruses requires merger of the viral envelope membrane with target cell membranes, resulting in the formation of fusion pores through which the viral genome is released. Since lipid membranes do not mix spontaneously, the fusion process is energy-dependent and mediated by viral envelope glycoprotein complexes. Based on their structural and mechanistic properties, three distinct classes of viral fusion proteins have been identified to date. Despite their diversity, basic principles of viral membrane fusion, simultaneous engagement of both donor and target membrane and refolding into hairpin-like structures, have emerged as universally conserved. This article provides an overview of the basic principles of viral membrane fusion common to all enveloped viruses and discusses the specific structural and functional features of the different fusion protein classes by example of the paramyxovirus, flavivirus and rhabdovirus families.

Figure 1

Schematic of viral membrane merger, exemplified by the paramyxovirus F protein. Upon fusion triggering, conformational changes of the native F glycoprotein result in an extended conformation, in which both viral envelope and target membrane are engaged (left panel). Through refolding of several F trimers, a fusion funnel with high local lipid curvature is thought to form. Merger of the outer monolayers of the approaching membranes creates a lipid stalk, which, according to the common stalk-diaphragm model, expands to hemifusion and formation of a hemifusion diaphragm (center panel). Completion of the F refolding into a thermodynamically stable hairpin structure is considered to advance merger to fusion pore formation and subsequent pore expansion (right panel).

Figure 2

Renderings of class I (paramyxovirus F (A)), class II (flavivirus E (B)) and class III (rhabdovirus G (C)) viral fusion proteins in the pre- and postfusion conformations. For clarity, high-resolution structural models were colored by monomer and then morphed into lower resolution images using the Sculptor (resolution 12, voxel size 3) software package [83]. Structures are based on PDB coordinates 2B9B and 1ZTM ([32,33] (A)), 1OAN and 1OK8 ([48,49] (B)), and 2J6J and 2CMZ ([62,63] (C)), respectively.

Figure 3

Schematic representation of the general domain organization and conformational reorganization of the three viral fusion protein classes. Fusion peptides/loops are highlighted in red. A) Paramyxovirus F: fusion peptide-proximal HR domains forming the central trimeric coiled coil (purple) and TMD-proximal HR domains (orange) are highlighted. B) Flavivirus E: the extended domains II harboring the fusion loops are highlighted (purple). C) Rhabdovirus G: the fusion domains (DIV, purple) and the trimerization domains (DII) refolding into the postfusion 6HB (orange) are highlighted.