Structure and Mechanism of a Coreceptor for Infection by a Pathogenic Feline Retrovirus

Abstract

Infection of T lymphocytes by the cytopathic retrovirus feline leukemia virus subgroup T (FeLV-T) requiresFeLIX, a cellular coreceptor that is encoded by an endogenous provirus and closely resembles the receptorbinding domain (RBD) of feline leukemia virus subgroup B (FeLV-B). We determined the structure of FeLV-B RBD, which has FeLIX activity, to a 2.5-Å resolution by X-ray crystallography. The structure of the receptorspecific subdomain of this glycoprotein differs dramatically from that of Friend murine leukemia virus (Fr-MLV), which binds a different cell surface receptor. Remarkably, we find that Fr-MLV RBD also activates FeLV-T infection of cells expressing the Fr-MLV receptor and that FeLV-B RBD is a competitive inhibitor of infection under these conditions. These studies suggest that FeLV-T infection relies on the following property of mammalian leukemia virus RBDs: the ability to couple interaction with one of a variety of receptors to the activation of a conserved membrane fusion mechanism. A comparison of the FeLV-B and Fr-MLV RBD structures illustrates how receptor-specific regions are linked to conserved elements critical for postbinding events in virus entry.Mammalian leukemia retroviruses, recently designated "␥-retroviruses" (gammaretroviruses) (22), have been widely dispersed by infection and by vertical transmission through the germ line. Glycoproteins that protrude from the gammaretrovirus membrane mediate entry into the cell during infection. These glycoproteins are trimers of heterodimers composed of surface (SU) and transmembrane (TM) subunits. The SU subunit contains an N-terminal domain that binds to receptor (6, 7, 15) and a C-terminal region that is disulfide bonded to the TM subunit, which mediates fusion between the virus and cell membranes. More than 10 subgroups of gammaretroviruses, distinguished by the specificity of their receptor-binding domains (RBDs), have been identified (44).Initial hypotheses for the mechanism of cell entry by gammaretroviruses supposed, by analogy to the hemagglutinin envelope protein of influenza virus (43,50), that the SU subunit functions as a clamp to suppress the membrane fusion activity of TM (20). In this scheme, binding of RBD to receptor would dissociate the three SU subunits, thereby releasing TM from a kinetically trapped, metastable conformation. Recent studies, however, require a modification of this view. Contrary to expectation, the addition of purified, monomeric RBD to the culture medium restores infection by mutant gammaretroviruses in which membrane fusion is uncoupled from receptor binding by deletion of the His residue in the conserved SerPro-His-Gln motif near the N terminus of the viral RBD (4,5,27,29). This observation excludes a simple model in which receptor binding activates the fusion machinery in TM by merely disrupting the quaternary structure of SU.

Conserved Receptor-binding Domains of Lake Victoria Marburgvirus and Zaire Ebolavirus Bind a Common Receptor

“…Receptor-binding regions of viral fusion proteins are typically the most important antibody-neutralizing epitopes on the virion, because of the functional importance of and limited variation in this region (44,45). In some cases, such as murine and feline leukemia viruses and SARS coronavirus, the receptor-binding region is localized to a discrete, independently folded domain that can efficiently bind the cellular receptor and inhibit infection (37,50,51). These domains themselves also can be sufficient to elicit protective neutralizing antibodies (45,52).…”

Change of Tropism of SL3-2 Murine Leukemia Virus, Using Random Mutational Libraries

“…The residues corresponding to SL3-2 R212 and T213 in Friend MLV, glycine at position 249 and arginine at position 250 (G215 and R216, as numbered in the coordinates of the pdb file obtained from The Protein Data Bank at http://www .rcsb.org/pdb/), and in feline leukemia virus subtype B, glycine at position 224 and tyrosine at position 225 (G190 and Y191, as numbered in the coordinates of the pdb file obtained from The Protein Data Bank), are found in small loops on the surface of the SU subunit, according to the crystal structures of the RBDs (6,18). The high degree of sequence identity at this region between Friend and SL3-2 viruses makes it likely that residues 212 and 213 in SL3-2 are also found on the surface of the protein, in which case these residues might be involved in a direct interaction with the receptor.…”

A soluble envelope protein of endogenous retrovirus (FeLIX) present in serum of domestic cats mediates infection of a pathogenic variant of feline leukemia virus

“…Although the FeLIXmediated infection process requires Pit1, FeLV-T RBD seems not to bind to Pit1 directly (Lauring et al, 2002). Furthermore, it was reported that infection by FeLV-T deleted of its RBD could be rescued by soluble cofactors, suggesting that FeLV-T does not require its cognate receptor but can use alternative receptors recognized by the soluble cofactors (Barnett et al, 2003). Because the receptor-independent infection process overcomes the receptor-interference, FeLV-T has a selective advantage in chronically infected cats.…”