Human cytomegalovirus US2 endoplasmic reticulum-lumenal domain dictates association with major histocompatibility complex class I in a locus-specificmanner

The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reti culum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome, We demonstrate that the endoplasmi c reticulum-lumenal domain of US2 allows tight interaction with class I mol ecules encoded by the HLA-A locus, Recombinant soluble US2 binds properly f olded, peptide-containing recombinant HLA-A2 molecules in a peptide sequenc e-independent manner, consistent with US2's ability to broadly downregulate class I molecules, The physicochemical properties of the US2/MHC class I c omplex suggest a 1:1 stoichiometry, These results demonstrate that US2 does not require additional cellular proteins to specifically interact with sol uble class I molecules. Binding of US2 does not significantly alter the con formation of class I molecules, as a soluble T-cell receptor can simultaneo usly recognize class I molecules associated with US2, The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US 2 binds several HLA-A locus products while being unable to bind recombinant HLA-B7, HLA-B27, HLA-Cw4, or HLA-E. We did not observe interaction between soluble US2 and either recombinant HLA-DR1 or recombinant HLA-DM, The subs trate specificity of US2 may help explain the presence in human cytomegalov irus of multiple strategies for down-regulation of MHC class I molecules.