Crystal structure of an NK cell immunoglobulin-like receptor in complex with its class I MHC ligand

Abstract

Target cell lysis is regulated by natural killer (NK) cell receptors that recognize class I MHC molecules. Here we report the crystal structure of the human immunoglobulin-like NK cell receptor KIR2DL2 in complex with its class I ligand HLA-Cw3 and peptide. KIR binds in a nearly orthogonal orientation across the alpha1 and alpha2 helices of Cw3 and directly contacts positions 7 and 8 of the peptide. No significant conformational changes in KIR occur on complex formation. The receptor footprint on HLA overlaps with but is distinct from that of the T-cell receptor. Charge complementarity dominates the KIR/HLA interface and mutations that disrupt interface salt bridges substantially diminish binding. Most contacts in the complex are between KIR and conserved HLA-C residues, but a hydrogen bond between Lys 44 of KIR2DL2 and Asn 80 of Cw3 confers the allotype specificity. KIR contact requires position 8 of the peptide to be a residue smaller than valine. A second KIR/HLA interface produced an ordered receptor-ligand aggregation in the crystal which may resemble receptor clustering during immune synapse formation.

Putative fasciclin-like arabinogalactan-proteins (FLA) in wheat (Triticum aestivum) and rice (Oryza sativa): identification and bioinformatic analyses

“…In this case the interacting surfaces are hydrophilic and rich in charged residues such as Trp, Tyr, Arg and Lys. Our understanding of the molecular basis of interactions mediated by plant fasciclin-like domains is limited, however, extrapolation of the work carried out on the animal fasciclin and immunoglobulin super-family (Boyington et al 2000;Wang et al 1999;Soroka et al 2002) to plant fasciclin domain model may allow predictions to be made concerning regions within the fold that mediate binding through homophilic (between similar fasciclin-like domains) or heterophilic (diVerent fasciclin-like domain or other interacting proteins) mechanism. Several AtFLA genes are found to be expressed at the same time and in the same tissues (according to the "A. thaliana Co-Response Database"), which may suggest the possibility of interaction between these FLA proteins via homophilic or heterophilic mechanisms.…”

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…Three key advancements have progressed understanding of the recognition of HLA class I by KIR; (i) the crystal structures of KIR in complex with their HLA class I ligands,10, 35, 70, 99 (ii) the development of soluble KIR36, 100, 101 and (iii) their use in a multiplex immunoassay against a broad panel of HLA class I allotypes102, 103 (Fig. 3).…”

“…Dimorphism at residue 44 of the KIR molecule causes these specificity differences, where KIR2DL2/3 has lysine and KIR2DL1 has methionine 36, 100, 104, 105. Crystal structures showed that K44 of KIR2DL2 forms a hydrogen bond with the N80 of HLA‐C1 99. By contrast, M44 of KIR2DL1 has no direct contact with HLA‐C but forms part of a charge pocket that accommodates the K80 of HLA‐C2 70.…”

“…Studies using soluble KIR showed that allotype KIR2DL3*001 is C1‐specific and binds relatively weakly, whereas KIR2DL2*001 binds more strongly and has cross‐reactivity with C2 103. In addition to those directly at the binding site, the substitutions that cause these functional differences may affect the angle or orientation of the binding domain,55, 103 or the efficiency of receptor clustering at the cell surface 99, 108. Allelic polymorphism also influences the functional properties of KIR2DL1, which has evolved to be a highly specific receptor for HLA‐C2 110.…”

Cis–trans interactions of cell surface receptors: biological roles and structural basis

“…For Ly49 receptors, it was shown that Ly49C in complex with H-2K b retains nearly the same structure as the free receptor [55], arguing against MHC-induced conformational changes in Ly49 as a signaling mechanism. On the other hand, monovalent human KIR-HLA-C complexes are thought to multimerize in a zinc-dependent fashion, and this seems to be needed for inhibitory signaling at the NK cell immune synapse [56]. Similarly, Ly49 signaling may depend on clustering of ligand-engaged Ly49 dimers.…”