title: Dimorphic motifs in D0 and D1+D2 domains of killer cell Ig-like receptor 3DL1 combine to form receptors with high, moderate, and no avidity for the complex of a peptide derived from HIV and HLA-A*2402.
abstract: 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.
authors.affiliation: Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Deepti
authors.initials: D
authors.lastname: Sharma
authors.forename: Karine
authors.initials: K
authors.lastname: Bastard
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.forename: Nobuyo
authors.initials: N
authors.lastname: Yawata
authors.forename: Makoto
authors.initials: M
authors.lastname: Yawata
authors.forename: Marcelo
authors.initials: M
authors.lastname: Pando
authors.forename: Hathairat
authors.initials: H
authors.lastname: Thananchai
authors.forename: Tao
authors.initials: T
authors.lastname: Dong
authors.forename: Sarah
authors.initials: S
authors.lastname: Rowland-Jones
authors.forename: Frances M
authors.initials: FM
authors.lastname: Brodsky
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology*; D000915:Antibody Affinity / Q000235:genetics; D015693:Gene Products, nef / Q000235:genetics* / Q000378:metabolism; D015234:HLA-A Antigens / Q000235:genetics* / Q000378:metabolism*; D059871:HLA-A24 Antigen; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007930:Leucine / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011110:Polymorphism, Genetic / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D054341:Receptors, KIR3DL1 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D014364:Tryptophan / Q000235:genetics / Q000378:metabolism
chemical_list: D015693:Gene Products, nef; D015234:HLA-A Antigens; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D008565:Membrane Proteins; D054341:Receptors, KIR3DL1; D014364:Tryptophan; D007930:Leucine