title: Structural elements underlying the high binding affinity of human cytomegalovirus UL18 to leukocyte immunoglobulin-like receptor-1.
abstract: 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 alpha1 and alpha3 domains, respectively, reduced binding affinity to LIR-1 nearly by half. The model also suggested the formation of an additional disulfide bridge in the alpha3 domain of UL18 between residues C240 and C255, not present in MHC-I. Substitution of either cysteine residue prevented association of UL18 to beta2m, abolishing binding to LIR-1. All observed differences in binding affinities translated directly into functional consequences in terms of inhibition of IFN-gamma production by T cells, mediated through the UL18-LIR-1 interaction. The larger amount of interacting regions, combined with an increased stability of the alpha3 and beta2m domains allow a higher recognition affinity of UL18 by LIR-1.
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Wagner
authors.forename: Alexander
authors.initials: A
authors.lastname: Rölle
authors.forename: David
authors.initials: D
authors.lastname: Cosman
authors.forename: Hans-Gustaf
authors.initials: HG
authors.lastname: Ljunggren
authors.forename: Kurt D
authors.initials: KD
authors.lastname: Berndt
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
mesh_terms: D015153:Blotting, Western; D017252:CD3 Complex / Q000378:metabolism; D036022:Capsid Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008213:Lymphocyte Activation; D011487:Protein Conformation; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism; D001613:beta 2-Microglobulin / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D036022:Capsid Proteins; D004220:Disulfides; D011971:Receptors, Immunologic; C079750:VP23 protein, Human herpesvirus 1; D001613:beta 2-Microglobulin; D007371:Interferon-gamma