Viral Membrane Fusion: A Dance Between Proteins and Lipids

Abstract

There are at least 21 families of enveloped viruses that infect mammals, and many contain members of high concern for global human health. All enveloped viruses have a dedicated fusion protein or fusion complex that enacts the critical genome-releasing membrane fusion event that is essential before viral replication within the host cell interior can begin. Because all enveloped viruses enter cells by fusion, it behooves us to know how viral fusion proteins function. Viral fusion proteins are also major targets of neutralizing antibodies, and hence they serve as key vaccine immunogens. Here we review current concepts about viral membrane fusion proteins focusing on how they are triggered, structural intermediates between pre- and postfusion forms, and their interplay with the lipid bilayers they engage. We also discuss cellular and therapeutic interventions that thwart virus-cell membrane fusion.

Structures of the Foamy virus fusion protein reveal an unexpected link with the F protein of paramyxo- and pneumoviruses

“…3C). This observation suggests that the domain IV ⍺ -helices may play the role of membrane-proximal regions (MPR), which can be involved in membrane destabilization during fusion (reviewed in [36]). Poor density was observed at the bottom of the maps of the pre-fusion Env ectodomain construct ( ab initi o models, classes 0 and 3, Fig.…”

Structure-based design of a soluble human cytomegalovirus glycoprotein B antigen stabilized in a prefusion-like conformation

“…This involves transitioning to an extended intermediate state, in which DI disengages from the MPR, rotates with DII approximately 180° relative to DIII, and embeds the fusion loops into the host-cell membrane (23). This intermediate, which bridges the viral and host-cell membranes, then collapses into the highly stable postfusion conformation, bringing the viral and host-cell membranes together to create a fusion pore (9,23). Two 3.6 Å resolution crystal structures of postfusion HCMV gB were published in 2015 (24,25) and these closely resembled the postfusion structures of gB homologs from herpes simplex virus type 1 (HSV-1) and Epstein-Barr virus (EBV) (26,27).…”

“…As a member of the Herpesviridae family, HCMV is an enveloped, double-stranded DNA virus ( 8 ). Viruses within this family enter host cells through a conserved mechanism, relying on the coordinated actions of multiple surface glycoproteins for receptor binding and membrane fusion ( 9 ). The specific receptors and glycoproteins involved vary among different herpesviruses, although glycoprotein B (gB), which mediates membrane fusion, is highly conserved and required for entry ( 10, 11 ).…”

“…HCMV gB is a class III fusion protein encoded by open reading frame UL55. Class III fusion proteins share features of both class I and class II fusion proteins, including trimeric central helices arranged in a coiled-coil and internal fusion loops ( 9, 20 ). Class III fusion proteins are found in herpesviruses, rhabdoviruses, thogotoviruses, and baculoviruses ( 9 ).…”

“…Class III fusion proteins share features of both class I and class II fusion proteins, including trimeric central helices arranged in a coiled-coil and internal fusion loops ( 9, 20 ). Class III fusion proteins are found in herpesviruses, rhabdoviruses, thogotoviruses, and baculoviruses ( 9 ). Upon translation of the monocistronic gB mRNA, each protomer undergoes extensive glycosylation, with high occupancy at the 17–18 predicted N-linked glycosylation sites per protomer ( 21 ) ( Figure 1A ).…”