Membrane fusion protein


Membrane fusion proteins are proteins that cause fusion of biological membranes. Membrane fusion is critical for many biological processes, especially in eukaryotic development and viral entry. Fusion proteins can originate from genes encoded by infectious enveloped viruses, ancient retroviruses integrated into the host genome, or solely by the host genome. Post-transcriptional modifications made to the fusion proteins by the host can drastically affect fusogenicity, namely addition and modification of glycans and acetyl groups.

Fusion in Eukaryotes

Eukaryotic genomes contain several gene families, of host and viral origin, which encode products involved in driving membrane fusion. While adult somatic cells do not typically undergo membrane fusion under normal conditions, gametes and embryonic cells follow developmental pathways to non-spontaneously drive membrane fusion, such as in placental formation, syncytiotrophoblast formation, and neurodevelopment. Fusion pathways are also involved in the development of musculoskeletal and nervous system tissues. Vesicle fusion events involved in neurotransmitter trafficking also relies on the catalytic activity of fusion proteins.

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Enveloped viruses readily overcome the thermodynamic barrier of merging two plasma membranes by storing kinetic energy in fusion proteins. F proteins can be independently expressed on host cell surfaces which can either drive the infected cell to fuse with neighboring cells, forming a syncytium, or be incorporated into a budding virion from the infected cell which leads to the full emancipation of plasma membrane from the host cell. Some F components solely drive fusion while a subset of F proteins can interact with host factors. There are four groups of F proteins categorized by their mechanism of fusion.

Class I

Class I fusion proteins resemble influenzavirus hemagluttinin in their structure. Post-fusion, the active site has a trimer of α-helical coiled-coils. The binding domain is rich in α-helices and hydrophobic fusion peptides located near the N-terminus. Fusion conformation change can be controlled by pH.
Fusion ComponentAbbreviationFamilyViruses
Hemagluttinin H, HNOrthomyxoviridae, ParamyxoviridaeInfluenza, Measles, Mumps
Glycoprotein 41Gp41RetroviridaeHIV

Class II

Class II proteins are dominant in β-sheets and the catalytic sites are localized in the core region. The peptide regions required to drive fusion are formed from the turns between the β-sheets.
Fusion ComponentAbbreviationFamilyViruses
Envelope proteinEFlaviviridaeDengue, West Nile virus

Class III

Class III fusion proteins are distinct from I and II. They typically consist of 5 structural domains, where domain 1 and 2 localized to the C-terminal end often contain more β-sheets and domains 2-5 closer to the N-terminal side are richer in α-helices. In the pre-fusion state, the later domains nest and protect domain 1. Domain 1 contains the catalytic site for membrane fusion.
Prototypic ExampleAbbreviationFamilyViruses
VSV GGRhabdoviridaeVesicular Stomatitis Virus, Rabies lyssavirus
HSV-1 gBgBHerpesviridaeHSV-1
Ebolavirus GlycoproteinGPFiloviridaeZaire-, Sudan- ebolaviruses, Marburgvirus

Class IV

Class IV are the smallest fusion proteins. They are also called fusion-associated small transmembrane proteins and are most often associated with non-enveloped reoviruses.