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All-Atom Simulations Reveal the Intricacies of Signal Transduction upon Binding of the HLA-E Ligand to the Transmembrane Inhibitory CD94/NKG2A Receptor
[Image: see text] 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 th...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268964/ https://www.ncbi.nlm.nih.gov/pubmed/37207294 http://dx.doi.org/10.1021/acs.jcim.3c00249 |
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author | Ljubič, Martin Prašnikar, Eva Perdih, Andrej Borišek, Jure |
author_facet | Ljubič, Martin Prašnikar, Eva Perdih, Andrej Borišek, Jure |
author_sort | Ljubič, Martin |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-10268964 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-102689642023-06-16 All-Atom Simulations Reveal the Intricacies of Signal Transduction upon Binding of the HLA-E Ligand to the Transmembrane Inhibitory CD94/NKG2A Receptor Ljubič, Martin Prašnikar, Eva Perdih, Andrej Borišek, Jure J Chem Inf Model [Image: see text] 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. American Chemical Society 2023-05-19 /pmc/articles/PMC10268964/ /pubmed/37207294 http://dx.doi.org/10.1021/acs.jcim.3c00249 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Ljubič, Martin Prašnikar, Eva Perdih, Andrej Borišek, Jure All-Atom Simulations Reveal the Intricacies of Signal Transduction upon Binding of the HLA-E Ligand to the Transmembrane Inhibitory CD94/NKG2A Receptor |
title | All-Atom Simulations Reveal the Intricacies of Signal
Transduction upon Binding of the HLA-E Ligand to the Transmembrane
Inhibitory CD94/NKG2A Receptor |
title_full | All-Atom Simulations Reveal the Intricacies of Signal
Transduction upon Binding of the HLA-E Ligand to the Transmembrane
Inhibitory CD94/NKG2A Receptor |
title_fullStr | All-Atom Simulations Reveal the Intricacies of Signal
Transduction upon Binding of the HLA-E Ligand to the Transmembrane
Inhibitory CD94/NKG2A Receptor |
title_full_unstemmed | All-Atom Simulations Reveal the Intricacies of Signal
Transduction upon Binding of the HLA-E Ligand to the Transmembrane
Inhibitory CD94/NKG2A Receptor |
title_short | All-Atom Simulations Reveal the Intricacies of Signal
Transduction upon Binding of the HLA-E Ligand to the Transmembrane
Inhibitory CD94/NKG2A Receptor |
title_sort | all-atom simulations reveal the intricacies of signal
transduction upon binding of the hla-e ligand to the transmembrane
inhibitory cd94/nkg2a receptor |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10268964/ https://www.ncbi.nlm.nih.gov/pubmed/37207294 http://dx.doi.org/10.1021/acs.jcim.3c00249 |
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