The D0 Domain of KIR3D Acts as a Major Histocompatibility Complex Class I Binding Enhancer

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  • Salim I. Khakoo
    Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305
  • Ron Geller
    Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305
  • Sunny Shin
    Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305
  • Jomaquai A. Jenkins
    Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305
  • Peter Parham
    Department of Structural Biology, and Department of Microbiology and Immunology, Stanford University School of Medicine, Sherman Fairchild Building, Stanford, CA 94305

説明

<jats:p>In contrast to the KIR2D:HLA-C interaction, little is known of KIR3DL1's interaction with HLA-B or the role of D0, the domain not present in KIR2D. Differences in the strength and specificity for major histocompatibility complex class I of KIR3DL1 and its common chimpanzee homologue Pt-KIR3DL1/2 were exploited to address these questions. Domain-swap, deletion, and site-directed mutants of KIR3DL1 were analyzed for HLA-B binding using a novel, positively signaling cell–cell binding assay. Natural ‘deletion’ of residues 50 and 51 from its D0 domain causes Pt-KIR3DL1/2 to bind Bw4+ HLA-B allotypes more avidly than does KIR3DL1. Deletion of these residues from KIR3DL1, or their substitution for alanine, enhanced binding of Bw4+ HLA-B. None of 15 different point mutations in D0 abrogated KIR3DL1 binding to Bw4+ HLA-B. In contrast point mutations in the D1 and D2 domains of KIR3DL1, made from knowledge of KIR2D:HLA-C interactions, disrupted binding to Bw4+ HLA-B. The results are consistent with a model in which D1 and D2 make the principal contacts between KIR3DL1 and HLA-B while D0 acts through a different mechanism to enhance the interaction. This modulatory role for D0 is compatible with natural loss of expression of the D0 domain, a repeated event in the evolution of functional KIR genes.</jats:p>

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