Structural plasticity of KIR2DL2 and KIR2DL3 enables altered docking geometries atop HLA-C

Shoeib Moradi,Sanda Stankovic,Andrew G Brooks,Jamie Rossjohn,Christelle Retière,Philippa M Saunders,Jacqueline Widjaja,Julian P Vivian,Phillip Pymm,Bruce J Maclachlan,Shea Cox-Livingstone,Lucy C Sullivan,Camilla Faoro,Geraldine M O’Connor

doi:10.1038/s41467-021-22359-x

Abstract

The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. KIR2DL2, KIR2DL3 and HLA-C1 are highly polymorphic, with this variation being associated with differences in the onset and progression of some human diseases. However, the molecular bases underlying these associations remain unresolved. Here, we determined the crystal structures of KIR2DL2 and KIR2DL3 in complex with HLA-C*07:02 presenting a self-epitope. KIR2DL2 differed from KIR2DL3 in docking modality over HLA-C*07:02 that correlates with variabilty of recognition of HLA-C1 allotypes. Mutagenesis assays indicated differences in the mechanism of HLA-C1 allotype recognition by KIR2DL2 and KIR2DL3. Similarly, HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells. These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition.

Highlights

The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules
The KIR2DL2-HLA-C*07:02-RL9 ternary complex was determined to 3.1 Å resolution and displayed unambiguous density at the KIR2DL2/HLA-C interface allowing for ready interpretation (Supplementary Table 1, Supplementary Fig. 1)
As the above observations were based on the KIR2DL recognition of HLA-C1 allotypes bound to a single peptide, we examined the extent to which differences between KIR2DL2 and KIR2DL3 could be modulated by peptide repertoire

Summary

Introduction

The closely related inhibitory killer-cell immunoglobulin-like receptors (KIR), KIR2DL2 and KIR2DL3, regulate the activation of natural killer cells (NK) by interacting with the human leukocyte antigen-C1 (HLA-C1) group of molecules. HLA-C1 allotypes differed markedly in their capacity to inhibit activation of primary NK cells These functional differences derive, in part, from KIR2DS2 suggesting KIR2DL2 and KIR2DL3 binding geometries combine with other factors to distinguish HLA-C1 functional recognition. Natural killer (NK) cells discriminate between healthy and infected or transformed cells using an array of germlineencoded inhibitory and activating receptors[1,2] Central to this process is the interaction between the killer cell immunoglobulin-like receptors (KIR) and their cognate ligands, human leukocyte antigen class I molecules (HLA-I)[3,4,5]. While the KIR2DL contacts with the α2-helix are conserved, interactions with both the peptide and the α1-helix vary, consistent with the ability of KIR2DL1 and 2DL2 to discriminate between HLA-C1 and HLA-

Methods

Results

Conclusion