20.500.12556/RUL-147225 All-atom simulations reveal the intricacies of signal transduction upon binding of the HLA-E ligand to the transmembrane inhibitory CD94/NKG2A receptor 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. cells ligands membranes peptides proteins receptors biokemija imuski odziv virusi bakterije simulacije receptorji true false true Angleški jezik Slovenski jezik Članek v reviji 2023-06-27 09:40:49 2023-06-27 09:40:50 2023-07-27 15:33:49 0000-00-00 00:00:00 2023 0 0 Str. 3486-3499 iss. 11 Vol. 63 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577 1549-960X 10.1021/acs.jcim.3c00249 154332419 acs.jcim.3c00249.pdf acs.jcim.3c00249.pdf 1 DD62CD9B8B57F24760EE18155EC88395 96213c330245c37e5aa31b7a919cf4db0da0527571f10910fd7901b457aaf6a3 9f009c07-14be-11ee-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=170719 https://pubs.acs.org/doi/10.1021/acs.jcim.3c00249 0 681a116a-14be-11ee-a314-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=170718 Fakulteta za farmacijo 0 0 0