Nonameric peptide orchestrates signal transduction in the activating hla‐e/nkg2c/cd94 immune complex as revealed by all‐atom simulations

Abstract

The innate immune system’s natural killer (NK) cells exert their cytolytic function against a variety of pathological challenges, including tumors and virally infected cells. Their activation depends on net signaling mediated via inhibitory and activating receptors that interact with specific lig-ands displayed on the surfaces of target cells. The CD94/NKG2C heterodimer is one of the NK activating receptors and performs its function by interacting with the trimeric ligand comprised of the HLA‐ E/β2m/nonameric peptide complex. Here, simulations of the all‐atom multi‐microsecond molecular dynamics in five immune complexes provide atomistic insights into the receptor–ligand molecular recognition, as well as the molecular events that facilitate the NK cell activation. We identify NKG2C, the HLA‐Eα2 domain, and the nonameric peptide as the key elements involved in the molecular ma-chinery of signal transduction via an intertwined hydrogen bond network. Overall, the study ad-dresses the complex intricacies that are necessary to understand the mechanisms of the innate immune system.