Receptor binding transforms the surface subunit of the mammalian C-type retrovirus envelope protein from an inhibitor to an activator of fusion

The envelope protein (Env) of murine leukemia viruses (MLVs) is composed of a surface subunit (SU) and a transmembrane subunit (TM), which mediates me mbrane fusion, resulting in infection. SU contains a discrete N-terminal re ceptor binding domain (RBD) that is connected to the remainder of Env by a short, proline-rich segment. Previous studies suggest that after receptor b inding, the RBD interacts directly with the remainder of Env to trigger fus ion (A. L. Barnett, R. A. Davey, and J. M. Cunningham, Proc. Natl. Acad. Sc i. USA 98:4113-4118, 2001). To investigate the role of the RBD in activatin g fusion, we compared infection by several MLVs that are defective unless r escued in trans by the addition of soluble RBD to the culture medium. Infec tion by MLV lacking a critical histidine residue near the N terminus of the viral RBD is dependent on the expression of receptors for both the RBD in the viral Env and the soluble RBD supplied in traits. However, infection by MLVs in which the RBD has been deleted or replaced by the ligand erythropo ietin are dependent only on expression of the receptor for the soluble RBD. We were able to expand the host range of xenotropic MLV to nonpermissive m urine fibroblasts only if the RBD was deleted from the xenotropic viral env elope and the soluble RBD from ecotropic Friend MLV was supplied to the cul ture medium. These findings indicate that receptor binding transforms the R BD from an inhibitor to an activator of the viral fusion mechanism and that viruses lacking the critical histidine residue at the N terminus of the RB D are impaired at the activation step.