1.G.12 The Avian Leukosis Virus gp95 Fusion Protein (ALV-gp95) Family

Retroviruses rely on low pH to activate their fusion proteins that merge the viral envelope with an endosomal membrane, releasing the viral nucleocapsid into the cytosol (Jha et al., 2011). The fusion process involves a relatively stable hemifusion-like intermediate that precedes fusion pore opening. EnvA (gp95) mediates entry through alternative receptor isoforms and intermediates of virus-endosome fusion (Jha et al., 2011). 

The long-hydrophobic viral fusion peptide (VFP) sequences are structurally constrained to access three successive states after biogenesis (Apellániz et al. 2014). Firstly, the VFP sequence must achieve a set of native interactions required for (meta) stable folding within the globular ectodomains of the glycoprotein complexes. Secondly, at the onset of the fusion process, these complexes get transferred into the target cell membrane and adopt specific conformations therein. According to commonly accepted mechanistic models, membrane-bound states of the VFP might promote the lipid bilayer remodeling required for virus-cell membrane merger. Finally, at least in some instances, several VFPs co-assemble with transmembrane anchors into membrane integral helical bundles, following a locking movement hypothetically coupled to fusion-pore expansion. Apellániz et al. 2014 reviewed different aspects of the three major states of the VFPs, including the functional assistance by other membrane-transferring glycoprotein regions. 



This family belongs to the Viral Envelope Fusion Protein (Env-FP) Superfamily.

 

References:

Apellániz, B., N. Huarte, E. Largo, and J.L. Nieva. (2014). The three lives of viral fusion peptides. Chem Phys Lipids 181: 40-55.

He, J., L.I. Melnik, A. Komin, G. Wiedman, T. Fuselier, C.F. Morris, C.G. Starr, P.C. Searson, W.R. Gallaher, K. Hristova, R.F. Garry, and W.C. Wimley. (2017). Ebola Virus Delta Peptide is a Viroporin. J. Virol. [Epub: Ahead of Print]

Jha, N.K., O. Latinovic, E. Martin, G. Novitskiy, M. Marin, K. Miyauchi, J. Naughton, J.A. Young, and G.B. Melikyan. (2011). Imaging single retrovirus entry through alternative receptor isoforms and intermediates of virus-endosome fusion. PLoS Pathog 7: e1001260.

Lee, J., A.J.B. Kreutzberger, L. Odongo, E.A. Nelson, D.A. Nyenhuis, V. Kiessling, B. Liang, D.S. Cafiso, J.M. White, and L.K. Tamm. (2021). Ebola virus glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry. Nat Struct Mol Biol 28: 181-189.

Examples:

TC#NameOrganismal TypeExample
1.G.12.1.1

Avian leukosis virus (RSV) envelope glycoprotein, gp95 or EnvA (606aas; 2 TMSs). Mediates pore formation preceded by a relatively stable hemifusion-like intermediate (Jha et al., 2011).  A shorter version is of 138 aas and has two TMSs at the N- and C-termini.  It's acc# is H7CEB0. The fusion peptide is 28 aas with a single TMS (Apellániz et al. 2014).

Viruses (Retroviridae)

EnvA of Rous sarcoma virus (Avian leukosis virus) (P03397)

 
Examples:

TC#NameOrganismal TypeExample
1.G.12.2.1

Cat envelope syncytin-Car1 protein, a fusogenic endogenous retrovirus-derived envelope protein

Mammals

Syncytin-Car1 of Felis catus

 
1.G.12.2.2

Ebola virus glycoportein 2 of 676 aas.  The NMR structure of the internal fusion loop of 54 aas has been solved (2LCY) The fusion peptide is 17 aas long (Apellániz et al. 2014). The GP2 protein also encoedes the GP2-δ peptide of 40 aas which is a viroporin (He et al. 2017). This nonstructural polypeptide, called the delta peptide, is produced in abundance during Ebola virus infection. Full length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells, increase ion permeability across confluent cell monolayers and permeabilize synthetic lipid bilayers. Permeabilization activity is dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity (He et al. 2017). 

Viruses (Filoviridae)

GP2 of Zaire Ebola virus

 
1.G.12.2.3

Glycoprotein 2, GP2, of 320 aas and 2 TMSs, one N-terminal and one C-terminal. A 3-stage mechanism of action has been discussed and reviewed (Apellániz et al. 2014) (see family description).

Viruses (Filoviridae)

GP2 of Llovia virus

 
1.G.12.2.4

Full virion envolope spike glycoprotein, GP1.2, of 681 aas.  The intervan fusion peptide is 15 aas long (Apellániz et al. 2014).

Viruses (Filoviridae)

GP1.2 of Ravn Virus

 
1.G.12.2.5

The small secreted glycoprotein GP2 of 364 aas, containing the viroporin, GP2-δ, the last 40 aas of GP2 of Zaire ebolavirus (He et al. 2017). This nonstructural polypeptide, called the delta peptide, is produced in abundance during Ebola virus infection. Full length and conserved C-terminal delta peptide fragments permeabilize the plasma membranes of nucleated cells, increase ion permeability across confluent cell monolayers and permeabilize synthetic lipid bilayers. Permeabilization activity is dependent on the disulfide bond between the two conserved cysteines. The conserved C-terminal portion of the peptide is biochemically stable in human serum, and most serum-stable fragments have full activity (He et al. 2017). This glycoprotein interacts with cholesterol to enhance membrane fusion and cell entry (Lee et al. 2021).

GP2 of Ebola virus (EBOV)