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.