Arenavirus species are endemic in rodent populations worldwide, and some viruses can be transmitted to humans to cause hemorrhagic fevers with up to 30% mortality. Entry of these viruses into its host cell is initiated by the virus envelope glycoprotein (GPC) binding to a host-cell receptor, transferrin receptor 1 (TfR1) in the pathogenic New World viruses and alpha-dystroglycan in the Old World viruses, upon which the virion particle is endocytosed. GPC-mediated fusion of the viral and endosomal membranes is activated by acidic pH in the maturing endosome.

The GPC complex contains a cleaved stable signal peptide (SSP) in addition to the canonical receptor-binding (G1) and transmembrane fusion (G2) subunits. SSP is essential for intracellular transport of the GPC complex to the cell surface and for its membrane-fusion activity.

Structural domains comprising this superfamily share the structure of the zinc binding domain of GPC, available data is derived from studies on Junin arenavirus (JUNV). The face of the domain that contains the two zinc-binding clusters is well conserved among arenaviruses, and cluster II serves as a binding site for Cys-57 in SSP. It is believed that the zinc-mediated anchoring of SSP contributes to positioning the ectodomain loop of SSP relative to the G2 ectodomain to modulate membrane fusion PMID:21068387.