Ligand presentation on a synthetic flexible hinge in Moloney murine leukemia virus SU supports entry via a heterologous receptor

The envelope protein of Moloney murine leukemia virus mediates entry into mCAT-expressing cells. Attempts to change its receptor usage through the insertion of ligands at various sites have been met with varying success. We have tested several sites in Env for insertion of apelin, a small peptide ligand of the G-protein-coupled receptor APJ. Although most of the chimeric envelopes had retained their ability to infect mouse cells none showed APJ-dependent entry. Insertion of a peptide linker Ser-Gly-Gly-Ser-Gly at either side of the apelin motif in one of the chimeric envelopes resulted in an ability of the chimeric envelope to bind to and infect cells through APJ although with low efficiency. Several linker sequences isolated by library selection for APJ-dependent infection were found to support entry, however none more efficiently than the original SGGSG-linker. Hence, the immediate context of ligand presentation is critical for infectivity via a heterologous receptor.