Journal
JOURNAL OF VIROLOGY
Volume 75, Issue 11, Pages 5197-5204Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.75.11.5197-5204.2001
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Funding
- NIAID NIH HHS [5R37-AI33456, R37 AI033456] Funding Source: Medline
- NICHD NIH HHS [K12 HD001255, K12-HD01255] Funding Source: Medline
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The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reticulum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome, We demonstrate that the endoplasmic reticulum-lumenal domain of US2 allows tight interaction with class I molecules encoded by the HLA-A locus, Recombinant soluble US2 binds properly folded, peptide-containing recombinant HLA-A2 molecules in a peptide sequence-independent manner, consistent with US2's ability to broadly downregulate class I molecules, The physicochemical properties of the US2/MHC class I complex suggest a 1:1 stoichiometry, These results demonstrate that US2 does not require additional cellular proteins to specifically interact with soluble class I molecules. Binding of US2 does not significantly alter the conformation of class I molecules, as a soluble T-cell receptor can simultaneously recognize class I molecules associated with US2, The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US2 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 substrate specificity of US2 may help explain the presence in human cytomegalovirus of multiple strategies for down-regulation of MHC class I molecules.
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