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* Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305;
Unité Mixte de Recherche Centre National de la Recherche Scientifique 6204, Faculté des Sciences et des Techniques, Université de Nantes, Nantes, France;
Histocompatibility, Immunogenetics, and Disease Profiling Laboratory, Stanford University School of Medicine, Stanford, CA 94304;
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, Oxford, United Kingdom; and
¶ Departments of Bioengineering and Therapeutic Sciences, and Microbiology and Immunology, University of California, San Francisco, CA 94143
Comparison of mutant killer cell Ig-like receptor (KIR) 3DL1*015 substituted at natural positions of variation showed that tryptophan/leucine dimorphism at position 283 uniquely changes receptor conformation and can strongly influence binding of the A24nef tetramer. Dimorphic motifs at positions 2, 47, and 54 in D0 and 182 and 283 in D1+D2 distinguish the two 3DL1 lineages, typified by 3DL1*005 and 3DL1*015. The interlineage recombinant, KIR3DL1*001, combines D0 of 3DL1*005 with D1+D2 of 3DL1*015 and binds A24nef more strongly than either parent. In contrast, the reciprocal recombinant with D0 from 3DL1*015 and D1+D2 from 3DL1*005 cannot bind A24nef. Thus, D0 polymorphism directly affects the avidity of the KIR3DL1 ligand binding site. From these observations, multiple sequence alignment, and homology modeling, we constructed structural models for KIR3DL1 and its complex with A24nef. In these models, D0, D1, and D2 come together to form a binding surface for A24nef, which is contacted by all three Ig-like domains. A central pocket binds arginine 83, the only Bw4 motif residue essential for KIR3DL1 interaction, similar to the binding of lysine 80 in HLA-C by KIR2DL1. Central to this interaction is a salt bridge between arginine 83 of Bw4 and glutamate 282 of 3DL1, which juxtaposes the functionally influential dimorphism at position 283. Further 3DL1 mutants were tested and shown to have A24nef-binding properties consistent with the models. A24nef was not bound by KIR3DS1, the activating counterpart of KIR3DL1. Moreover, introducing any one of three residues specific to KIR3DS1, serine 163, arginine 166, or leucine 199, into 3DL1*015, abrogated A24nef binding.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grant AI064520 (to F.M.B. and P.P.). K.B. is a recipient of Marie Curie Fellowship MOIF-2005-022323.
2 D.S. and K.B. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Peter Parham, Stanford University School of Medicine, Sherman Fairchild Building 299 Campus Drive West, Stanford, CA 94305-5126. E-mail address: peropa{at}stanford.edu
4 Abbreviations used in this paper: KIR, killer cell Ig-like receptor; EGFP, enhanced GFP; mfi, mean fluorescence intensity; PDB, Protein Data Bank.
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