Differential recognition of Old World and New World arenavirus envelope glycoproteins by subtilisin kexin isozyme 1 (SKI-1)/site 1 protease (S1P).

The arenaviruses are an important family of emerging viruses including several causative agents of severe hemorrhagic fevers in humans that represent serious public health problems. A crucial step of the arenavirus life cycle is maturation of the envelope glycoprotein precursor (GPC) by the cellular subtilisin kexin isozyme-1 (SKI-1)/site-1 protease (S1P). Comparison of the currently known sequences of arenavirus GPCs revealed the presence of a highly conserved aromatic residue at position P7 relative to the SKI-1/S1P cleavage side in Old World and Clade C New World arenaviruses, but not in New World viruses of Clades A and B, or cellular substrates of SKI-1/S1P. Using a combination of molecular modeling and structure-function analysis, we found that residueY285 of SKI-1/S1P, distal of the catalytic triad, is implicated in the molecular recognition of the aromatic "signature residue" at P7 in the GPC of the Old World Lassa virus (LASV). Using a quantitative biochemical approach, we show that Y285 of SKI-1/S1P is crucial for efficient processing of peptides derived from Old World and Clade C New World arenaviruses, but not Clade A and B New World arenavirus GPCs. The data suggest that during co-evolution with their mammalian hosts, GPCs of Old World and Clade C New World viruses expanded the molecular contacts with SKI-1/S1P beyond the classical four amino acid recognition sequences and currently occupy an extended binding pocket.