The Structure of the Cytomegalovirus-Encoded m04 Glycoprotein, a Prototypical Member of the m02 Family of Immunoevasins

Background: Cytomegalovirus-encoded m02 family members are involved in immune evasion. Results: m04 binds murine MHC-I via an Ig-V-like ectodomain. Conclusion: m04 is the prototype of the m02 family, whose members mimic proteins derived from the host immune system. Significance: The results provide insight into the structural scaffold that defines a large family of immunoevasins. The ability of CMVs to evade the immune system of the host is dependent on the expression of a wide array of glycoproteins, many of which interfere with natural killer cell function. In murine CMV, two large protein families mediate this immune-evasive function. Although it is established that the m145 family members mimic the structure of MHC-I molecules, the structure of the m02 family remains unknown. The most extensively studied m02 family member is m04, a glycoprotein that escorts newly assembled MHC-I molecules to the cell surface, presumably to avoid missing self recognition. Here we report the crystal structure of the m04 ectodomain, thereby providing insight into this large immunoevasin family. m04 adopted a -sandwich immunoglobulin variable (Ig-V)-like fold, despite sharing very little sequence identity with the Ig-V superfamily. In addition to the Ig-V core, m04 possesses several unique structural features that included an unusual -strand topology, a number of extended loops and a prominent -helix. The m04 interior was packed by a myriad of hydrophobic residues that form distinct clusters around two conserved tryptophan residues. This hydrophobic core was well conserved throughout the m02 family, thereby indicating that murine CMV encodes a number of Ig-V-like molecules. We show that m04 binds a range of MHC-I molecules with low affinity in a peptide-independent manner. Accordingly, the structure of m04, which represents the first example of an murine CMV encoded Ig-V fold, provides a basis for understanding the structure and function of this enigmatic and large family of immunoevasins.