KIR2DS4 is a product of gene conversion with KIR3DL2 that introduced specificity for HLA-A*11 while diminishing avidity for HLA-C.
Human killer cell immunoglobulin-like receptors (KIRs) are distinguished by expansion of activating KIR2DS, whose ligands and functions remain poorly understood. The oldest, most prevalent KIR2DS is KIR2DS4, which is represented by a variable balance between "full-length" and "deleted" forms. We find that full-length 2DS4 is a human histocompatibility leukocyte antigen (HLA) class I receptor that binds specifically to subsets of C1+ and C2+ HLA-C and to HLA-A*11, whereas deleted 2DS4 is nonfunctional. Activation of 2DS4+ NKL cells was achieved with A*1102 as ligand, which differs from A*1101 by unique substitution of lysine 19 for glutamate, but not with A*1101 or HLA-C. Distinguishing KIR2DS4 from other KIR2DS is the proline-valine motif at positions 71-72, which is shared with KIR3DL2 and was introduced by gene conversion before separation of the human and chimpanzee lineages. Site-directed swap mutagenesis shows that these two residues are largely responsible for the unique HLA class I specificity of KIR2DS4. Determination of the crystallographic structure of KIR2DS4 shows two major differences from KIR2DL: displacement of contact loop L2 and altered bonding potential because of the substitutions at positions 71 and 72. Correlation between the worldwide distributions of functional KIR2DS4 and HLA-A*11 points to the physiological importance of their mutual interaction.
Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Thorsten
T
Graef
Achim K
AK
Moesta
Paul J
PJ
Norman
Laurent
L
Abi-Rached
Luca
L
Vago
Anastazia M
AM
Older Aguilar
Michael
M
Gleimer
John A
JA
Hammond
Lisbeth A
LA
Guethlein
David A
DA
Bushnell
Philip J
PJ
Robinson
Peter
P
Parham
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001665:Binding Sites; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D019143:Evolution, Molecular; D005785:Gene Conversion; D015234:HLA-A Antigens / Q000276:immunology*; D059870:HLA-A11 Antigen; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D002679:Pan troglodytes / Q000276:immunology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D054340:Receptors, KIR / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D054347:Receptors, KIR3DL2 / Q000235:genetics*; D013379:Substrate Specificity
D015234:HLA-A Antigens; D059870:HLA-A11 Antigen; D015236:HLA-C Antigens; C473953:KIR2DS4 protein, human; D008024:Ligands; D054340:Receptors, KIR; D054347:Receptors, KIR3DL2