Nonameric Peptide Orchestrates Signal Transduction in the Activating HLA-E/NKG2C/CD94 Immune Complex as Revealed by All-Atom Simulations.
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ABSTRACT:
SUBMITTER: Prasnikar E
PROVIDER: S-EPMC8268078 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: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.
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Project description:Natural killer (NK) cells play an important role in the innate immune response against tumors and various pathogens such as viruses and bacteria. Their function is controlled by a wide array of activating and inhibitory receptors, which are expressed on their cell surface. Among them is a dimeric NKG2A/CD94 inhibitory transmembrane (TM) receptor which specifically binds to the non-classical MHC I molecule HLA-E, which is often overexpressed on the surface of senescent and tumor cells. Using the Alphafold 2 artificial intelligence system, we constructed the missing segments of the NKG2A/CD94 receptor and generated its complete 3D structure comprising extracellular (EC), TM, and intracellular regions, which served as a starting point for the multi-microsecond all-atom molecular dynamics simulations of the receptor with and without the bound HLA-E ligand and its nonameric peptide. The simulated models revealed that an intricate interplay of events is taking place between the EC and TM regions ultimately affecting the intracellular immunoreceptor tyrosine-based inhibition motif (ITIM) regions that host the point at which the signal is transmitted further down the inhibitory signaling cascade. Signal transduction through the lipid bilayer was also coupled with the changes in the relative orientation of the NKG2A/CD94 TM helices in response to linker reorganization, mediated by fine-tuned interactions in the EC region of the receptor, taking place after HLA-E binding. This research provides atomistic details of the cells' protection mechanism against NK cells and broadens the knowledge regarding the TM signaling of ITIM-bearing receptors.
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Project description:MHC class I antigen E (HLA-E), a ligand for the inhibitory NKG2A/CD94 receptor of the immune system, is responsible for evading the immune surveillance in several settings, including senescent cell accumulation and tumor persistence. The formation of this ligand-receptor interaction promotes the inhibition of the cytolytic action of immune system natural killer (NK) cells and CD8+ T-cells expressing this receptor. The final outcome of the HLA-E/NKG2A/CD94 interaction on target cells is also highly dependent on the identity of the nonameric peptide incorporated into the HLA-E ligand. To better understand the role played by a nonameric peptide in these immune complexes, we performed a series of multi-microsecond all-atom molecular dynamics simulations. We generated natural and alternative variants of the nonameric peptide bound to the HLA-E ligand alone or in the HLA-E/NKG2A/CD94 complexes. A systematic study of molecular recognition between HLA-E and peptides led to the development of new variants that differ at the strategic 6th position (P6) of the peptide and have favorable in silico properties comparable to those of natural binding peptides. Further examination of a selected subset of peptides in full complexes revealed a new variant that, according to our previously derived atomistic model, can interfere with the signal transduction via HLA-E/NKG2A/CD94 and thus prevent the target cell from evading immune clearance by NK and CD8+ T-cells. These simulations provide an atomistic picture of how a small change in amino acid sequence can lead to a profound effect on binding and molecular recognition. Furthermore, our study also provides new data on the peptide interaction motifs as well as the energetic and conformational properties of the binding interface, laying the structure-based foundation for future development of potential therapeutic peptides, peptidomimetics, or even small molecules that would bind to the HLA-E ligand and abrogate NKG2A/CD94 recognition. Such external intervention would be useful in the emerging field of targeting senescent cells in a variety of age-related diseases, as well as in novel cancer immunotherapies.
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Project description:Psoriasis is an inflammatory, immune-mediated disease of the skin. Several studies have suggested that natural killer (NK) cells and their receptors may be important for its pathogenesis. Here, we examined whether deletion of the activating natural killer receptor gene NKG2C, which has a frequency of 20% in the European population, was associated with psoriasis susceptibility. The NKG2C deletion and a functional polymorphism in its ligand HLA-E were genotyped in a Caucasian cohort of 611 psoriasis cases and 493 controls. We found that the NKG2C deletion was significantly increased in cases compared with controls [0.258 vs 0.200, P = 0.0012, OR = 1.43 (1.15-1.79)]. The low-expressing HLA-E*01:01 allele was associated with psoriasis (P = 0.0018), although this association was dependent on HLA-C. Our findings support a potential immunoregulatory role for NK cells in psoriasis and suggest the importance of future studies to investigate the contribution of NK cells and their regulatory receptors to the pathogenesis of psoriasis.
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