1.G.3 The Viral Pore-forming Membrane Fusion Protein-3 (VMFP3) Family

The tick-borne encephalitis virus (TBEV) is a Class II fusion protein, consisting primarily of β-sheet structure with internal fusion peptides forming loops at the tips of β-strands. These proteins are in the virion, parallel to the viral membrane. There they exist as dimers that become β-stranded trimers upon membrane insertion and fusion (White et al. 2008). Fusion function depends on proteolytic processing. Other Class II VFPs include SFV E1/E2.

The flavivirus dengue virus (DV) infects cells through a low-pH-triggered membrane fusion reaction mediated by the viral envelope protein E. E is an elongated transmembrane protein with three C-terminal TMSs and is organized as a homodimer on the mature virus particle. During fusion, the E protein homodimer dissociates, inserts the hydrophobic fusion loop into target membranes, and refolds into a trimeric hairpin in which domain III (DIII) packs against the central trimer. It is clear that E refolding drives membrane fusion. Liao et al. (2010) used truncated forms of the DV E protein to reconstitute trimerization in vitro. Protein constructs containing domains I and II (DI/II) were monomeric and interacted with membranes to form core trimers. DI/II-membrane interaction and trimerization occurred efficiently at both neutral and low pH. The DI/II core trimer was relatively unstable and could be stabilized by binding exogenous DIII or by the formation of mixed trimers containing DI/II plus E protein with all three TMSs. The mixed trimer has unoccupied DIII interaction sites that specifically bind exogenous DIII at either low or neutral pH. Protein constructs containing domains I and II (DI/II) were monomeric and interacted with membranes to form core trimers. DI/II-membrane interaction and trimerization occurred efficiently at both neutral and low pH. The DI/II core trimer was relatively unstable and could be stabilized by binding exogenous DIII or by the formation of mixed trimers containing DI/II plus E protein with all three TMSs. The mixed trimer has unoccupied DIII interaction sites that specifically bind exogenous DIII at either low or neutral pH. Truncated DV E proteins thus reconstitute hairpin formation and define properties of key domain interactions during DV fusion.



This family belongs to the .

 

References:

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

Leung, J.Y., G.P. Pijlman, N. Kondratieva, J. Hyde, J.M. Mackenzie, and A.A. Khromykh. (2008). Role of nonstructural protein NS2A in flavivirus assembly. J. Virol. 82: 4731-4741.

Liao, M., C. Sánchez-San Martín, A. Zheng, and M. Kielian. (2010). In vitro reconstitution reveals key intermediate states of trimer formation by the dengue virus membrane fusion protein. J. Virol. 84: 5730-5740.

Shrivastava, G., J. García-Cordero, M. León-Juárez, G. Oza, J. Tapia-Ramírez, N. Villegas-Sepulveda, and L. Cedillo-Barrón. (2017). NS2A comprises a putative viroporin of Dengue virus 2. Virulence 8: 1450-1456.

White, J.M., S.E. Delos, M. Brecher, and K. Schornberg. (2008). Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit. Rev. Biochem. Mol. Biol. 43: 189-219.

Zhang, X., R. Jia, H. Shen, M. Wang, Z. Yin, and A. Cheng. (2017). Structures and Functions of the Envelope Glycoprotein in Flavivirus Infections. Viruses 9:.

Examples:

TC#NameOrganismal TypeExample
1.G.3.1.1

Tick-borne encephalitis virus (TBEV) (Class II) polyprotein of 3414 aas.  Residues 281 - 776 include the envelop protein that includes the viral fusion protein (Zhang et al. 2017).

Virus

Tick-borne encephalitis virus polyprotein (P14336)

 
1.G.3.1.2

Polyprotein (3391aas) (includes the membrane fusion protein, envelope protein E (495aas; 38% identical to residues 282-774 in 1.G.3.1.1) (Liao et al., 2010)).  The fusion peptides are residues 98 - 113 in V7SFC4 and residues 378 - 393 in P14340 (Apellániz et al. 2014).

Virus

Polyprotein of Dengue virus (P14340)
Envelope protein E (B7SFC4)

 
1.G.3.1.3

Polyprotein of 3432 aas of the Flavi-glycoprotein family.  The type II fusion peptide is residues 392 - 407 (Apellániz et al. 2014).

Viruses (Flaviviridae)

Polyprotein of Japanese encephalitis virus

 
1.G.3.1.4

Non-structural protein 2B of 131 aas and 2 TMSs.

NS2B of Usutu virus

 
1.G.3.1.5

NS2B of 131 aas and 2 TMSs.

NS2B of Murray Valley encephalitis virus

 
1.G.3.1.6

NS2A viroporin of 218 aas and 4 - 8 TMSs (Shrivastava et al. 2017).

NS2A of Dengue Virus

 
1.G.3.1.7

Polyprotein of 3433 aas and about 20 - 24 TMSs.  It includes the N2Sa protein which has been shown to be a viroporin (Leung et al. 2008).

N2Sa of Kunjin Virus