All-Atom Simulations Reveal a Key Interaction Network in the HLA-E/NKG2A/CD94 Immune Complex Fine-Tuned by the Nonameric Peptide.

Eva Prašnikar,Jure Borišek,Andrej Perdih

doi:10.1021/acs.jcim.1c00414

Abstract

Natural killer (NK) cells, an important part of the innate immune system, can clear a wide variety of pathological challenges, including tumor, senescent, and virally infected cells. They express various activating and inhibitory receptors on their surface, and the balance of interactions between them and specific ligands displayed on the surface of target cells is critical for NK cell cytolytic function and target cell protection. The CD94/NKG2A heterodimer is one of the inhibitory receptors that interacts with its trimeric ligand consisting of HLA-E, β2m, and a nonameric peptide. Here, multi-microsecond-long all-atom molecular dynamics simulations of eight immune complexes elucidate the subtleties of receptor (NKG2A/CD94)–ligand (HLA-E/β2m/peptide) molecular recognition that mediate the NK cell protection from a geometric and energetic perspective. We identify key differences in the interactions between the receptor and ligand complexes, which are via an entangled network of hydrogen bonds fine-tuned by the ligand-specific nonameric peptide. We further reveal that the receptor protein NKG2A regulates the NK cell activity, while its CD94 partner forms the majority of the energetically important interactions with the ligand. This knowledge rationalizes the atomistic details of the fundamental NK cell protection mechanism and may enable a variety of opportunities in rational-based drug discovery for diverse pathologies including viral infections and cancer and elimination of senescent cells associated with potential treatment of many age-related diseases.

Highlights

Natural killer (NK) cells are a subpopulation of lymphocytes, an important part of the innate immune system, that respond quickly without priming or preactivation to a wide variety of pathological challenges such as virally infected and tumor cells.[1]
We identified a hydrogen bonding network between CD94 and NKG2A that occurred more frequently in complexes with nonameric peptides, which effectively mediates the receptor−ligand recognition, allowing successful protection from NK cell elimination
We took into account only the resolved extracellular domains of proteins CD94, NKG2A, HLAE (2−274), and β2m deprived of its signal peptide, for which structural data are available

Summary

Introduction

Natural killer (NK) cells are a subpopulation of lymphocytes, an important part of the innate immune system, that respond quickly without priming or preactivation to a wide variety of pathological challenges such as virally infected and tumor cells.[1] They act through various molecule-specific receptors expressed on their surface, either via antibody-dependent or natural cytotoxicity.[2] In the latter case, the balance between interactions with inhibitory and activating receptors is crucial for the cytolytic function of the NK cells They present various inhibitory (e.g., CD94/NKG2A, -B, KIR2DL, and KIR3DL) or activating (e.g., NKG2D/NKG2D, KIR2DS, CD94/NKG2C, -E, and -H) receptors[3,4] that allow them to directly recognize ligands (proteins) expressed on the target cells and determine their fate. Cellular stress (e.g., DNA damage response, senescence program, tumor expression, viral infection, etc.) leads to the upregulation of expression of ligands for activating receptors (e.g., MIC-A/-B and ULBPs) or downregulation of normally present MHC class I molecules, shifting the balance in favor of NK cell activation and elimination of compromised cells.[2,5]

Methods

Results

Conclusion