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1.G: Viral Fusion Pores

The fusion of two membranes into one is an event shared by intracellular trafficking, fertilization, tissue formation, and viral infection (Earp et al., 2005Jahn et al., 2003; Mohler et al., 2002). On a structural level, fusion results in the unification of the lipid and protein components of the two membranes and the intermixing of the volumes initially bound by them. During membrane fusion, the proximal leaflets of the two membranes merge first, whereas the distal membrane leaflets remain separate until the opening of a fusion pore (Chernomordik and Kozlov, 2005). This intermediate stage, called hemifusion, is a critical event shared by exocytosis, protein trafficking, and viral entry.

Three distinct classes of viral membrane fusion proteins have been identified based on structural criteria. In addition, there are at least four distinct mechanisms by which viral fusion proteins can be triggered to undergo fusion-inducing conformational changes. Viral fusion proteins also contain different types of fusion peptides and vary in their reliance on accessory proteins. These differing features combine to yield a rich diversity of fusion proteins. Yet despite this staggering diversity, all characterized viral fusion proteins convert from a fusion-competent state (dimers or trimers, depending on the class) to a membrane-embedded homotrimeric prehairpin, and then to a trimer-of-hairpins that brings the fusion peptide, attached to the target membrane, and the transmembrane domain, attached to the viral membrane, into close proximity, thereby facilitating the union of viral and target membranes. During these conformational conversions, the fusion proteins induce membranes to progress through stages of close apposition, hemifusion, and then the formation of small, and finally large, fusion pores. Clearly, highly divergent proteins have converged on the same overall strategy to mediate fusion, an essential step in the life cycle of every enveloped virus. (White et al., 2008).

White et al 2008 summarize the properties of fusion proteins from fusion proteins of different families of enveloped viruses. The native proteins are proteolytically processed to generate the pore-forming fusion proteins. The native proteins are provided below. Information on these proteins is provided in Table 1 (White et al., 2008).

 

TABLE 1 Fusion proteins from different families of enveloped viruses
Family Proteins Needed Fusion Protein fusion subunit Class Fusion pH Fusion Peptide Location

Information is given for 13 of the 17 families of enveloped viruses and is updated from Table 1 of (Earp et al., 2005). Viruses in parentheses represent examples. NC, not classified. See text for more details.

(a) SU/TM, S1/S2, etc. denote that the indicated subunits are associated, but not disulfide bonded.

(b) Some family members fuse at neutral pH, while others require low pH, in some cases in addition to receptor binding. In the case of herpesviruses, cell type differences have been seen. A need for low pH for fusion of some paramyxoviruses with cells is under investigation (see text).

(c) Paramyxovirus receptor binding (attachment) proteins are denoted HN, H, or G depending on the virus.

(d) Ebola virus requires low endosomal pH for entry but the only confirmed low pH requirement is for the activity of endosomal cathepsins.

(e) Two regions of the Lassa Fever virus GP2, one at and one very close to its N-terminus, have been implicated in fusion (Klewitz et al., 2007), but more work is needed to clarify the locations of arenavirus fusion peptides.

(f) For HCV, several regions in E1 and E2 have been implicated (Lavillette et al., 2007; Poumbourios and Drummer, 2007).

(g) These entries are based only on a predictive analysis (Garry and Garry, 2004).

(h) gB is central to fusion and is a Class III fusion protein, but the gH/gL complex also participates.

(i) Vaccinia virus employs a complex of eight (Wagenaar and Moss, 2007), and perhaps additional (Kochan et al., 2007) proteins.

(j) These are tentative assignments based in part on observations suggesting a need for proteolytic processing within S during virus entry (Glebe and Urban, 2007; Li et al., 2004; Maenz et al., 2007).

Orthomyxoviridae HA HA1-S-S-HA2 I Low N-terminal
Retroviridae Env SU-S-S-TM, SU/TMa I Neutral (Low)b N-terminal (most)
          Internal (ASLV)
Paramyxoviridae F, HNc F2-S-S-F1 I Neutralb N-terminal
Coronaviridae S S1/S2 I Neutral (Low)b Internal
Filoviridae GP GP1-S-S-GP2 I Lowd Internal
Arenaviridae GP, SSP GP1/GP2/SSP I Low (N-terminal)e
Togaviridae E1/E2 E1/E2 II Low Internal
Flaviviridae E(TBEV), E1/E2 (HCV) E, E1/E2f II Low Internal
Bunyaviridae GN/GC GN/GCg IIg Low Internalg
Rhabdoviridae G G III Low Internal (bipartite)
Herpesviridae gB, gD, gH/L gBh, gH/gL III Neutral (Low)b Internal (bipartite)
Poxviridae 8 proteinsi nd NC Neutral (Low)b nd
Hepadnaviridae S, Lj Sj NC Lowj (N-terminal)j