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1.G.4 The Viral Pore-forming Membrane Fusion Protein-4 (VMFP4) Family

Many envelope viruses enter host cells via the endocytotic pathway. The virus is internalized via coated vesicles and transferred to endosomes. Due to the acidic conditions, the envelope of the virus fuses with the endosomal membrane. In Semliki Forest virus (SFV), fusion is mediated by the trimeric type I glycoprotein E1, which is initially complexed with other proteins (i.e., E2 and E3). These dissociate under acidic conditions. E1 has been shown to form pores in both animal cell and E. coli membranes under low pH (pH 6) conditions (Nyfeler et al. 2001). No other viral protein is required for pore formation. E1 (341 aas) is derived from the C-terminal region of the polyprotein of SMV. E1 shows a high degree of sequence identity with homologues from many other viruses.

The 6K proteins of two Alphaviruses, Ross River virus and Barmah Forest virus (derived from polyproteins of about 1250 aas) have been shown to form cation-selective channels in planar lipid bilayers. The purified proteins (of 60 and 58 aas, respectively) gave conductances that varied from 40 to 800 picosiemens, suggesting that they can form channels with a range of oligomeric states (Melton et al. 2002).

The reaction catalyzed by these cation-selective channels is:

ions (in) ⇌ ions (out)

References associated with 1.G.4 family:

Apellaniz B., Huarte N., Largo E. and Nieva JL. (2014). The three lives of viral fusion peptides. Chem Phys Lipids. 181:40-55. 24704587
Elmasri, Z., V. Negi, R.J. Kuhn, and J. Jose. (2022). Requirement of a functional ion channel for Sindbis virus glycoprotein transport, CPV-II formation, and efficient virus budding. PLoS Pathog 18: e1010892. 36191050
Gibbons, D.L., M.C. Vaney, A. Roussel, A. Vigouroux, B. Reilly, J. Lepault, M. Kielian, and F.A. Rey. (2004). Conformational change and protein-protein interactions of the fusion protein of Semliki Forest virus. Nature 427: 320-325. 14737160
Huang, T.C. and W.B. Fischer. (2022). Predicting the Assembly of the Transmembrane Domains of Viral Channel Forming Proteins and Peptide Drug Screening Using a Docking Approach. Biomolecules 12:. 36551274
Hyser, J.M. and M.K. Estes. (2015). Pathophysiological Consequences of Calcium-Conducting Viroporins. Annu Rev Virol 2: 473-496. 26958925
Melton, J.V., G.D. Ewart, R.C. Weir, P.G. Board, E. Lee, and P.W. Gage. (2002). Alphavirus 6K proteins form ion channels. J. Biol. Chem. 277: 46923-46931. 12228229
Nyfeler, S., K. Senn, and C. Kempf. (2001). Expression of Semliki Forest virus E1 protein in Escherichia coli. Low pH-induced pore formation. J. Biol. Chem. 276: 15453-15457. 11278826