Structural elements underlying the high binding affinity of human cytomegalovirus UL18 to leukocyte immunoglobulin-like receptor-1

CS Wagner, A Rölle, D Cosman, HG Ljunggren… - Journal of molecular …, 2007 - Elsevier
CS Wagner, A Rölle, D Cosman, HG Ljunggren, KD Berndt, A Achour
Journal of molecular biology, 2007Elsevier
Human cytomegalovirus (HCMV) encodes UL18, a major histocompatibility complex (MHC)
class I homologue that binds to the leukocyte immunoglobulin-like receptor (LIR)-1 (also
called ILT2/CD85j/LILRB1), an inhibitory receptor expressed on myeloid and lymphoid
immune cells. The molecular basis underlying the high affinity binding of UL18 to LIR-1,
compared to MHC class I molecules (MHC-I), is unclear. Based on a comparative structural
analysis of a molecular model of UL18 with the crystal structure of the HLA-A2/LIR-1 …
Human cytomegalovirus (HCMV) encodes UL18, a major histocompatibility complex (MHC) class I homologue that binds to the leukocyte immunoglobulin-like receptor (LIR)-1 (also called ILT2/CD85j/LILRB1), an inhibitory receptor expressed on myeloid and lymphoid immune cells. The molecular basis underlying the high affinity binding of UL18 to LIR-1, compared to MHC class I molecules (MHC-I), is unclear. Based on a comparative structural analysis of a molecular model of UL18 with the crystal structure of the HLA-A2/LIR-1 complex, we identified three regions in UL18 influencing interaction with LIR-1. Comparison of the relative binding affinities of mutated UL18 proteins to LIR-1 demonstrated the importance of specific residues in each region. Substitution of residues K42/A43 and Q202, localized in the α1 and α3 domains, respectively, reduced binding affinity to LIR-1 nearly by half. The model also suggested the formation of an additional disulfide bridge in the α3 domain of UL18 between residues C240 and C255, not present in MHC-I. Substitution of either cysteine residue prevented association of UL18 to β2m, abolishing binding to LIR-1. All observed differences in binding affinities translated directly into functional consequences in terms of inhibition of IFN-γ production by T cells, mediated through the UL18-LIR-1 interaction. The larger amount of interacting regions, combined with an increased stability of the α3 and β2m domains allow a higher recognition affinity of UL18 by LIR-1.
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