Abstract

Leukocytes in human bodies (such as T cell, natural killer (NK) cell, etc.) play key roles in screening cells infected by virus and sweeping them off. They behave like the ‘policemen’ and defend against the ‘invaders’ who intend to cause disease or damage our bodies. So how the ‘policemen’ accurately discriminate, arrest, and then eliminate the ‘invaders’?

In most cases, it’s hard to distinguish the ‘invaders’ because of their similarity with the normal cells. However, there exhibit specific markers on ‘invaders’, which can be discriminated by membrane receptors on ‘policemen’ with hypersensitivity. Thus, we focused on the underlying mechanism of membrane receptors discriminating specific ligands, and published the research paper titled ‘NKG2D discriminates diverse ligands through selectively mechano-regulated ligand conformational changes’ in the international professional academic journal "EMBO JOURNAL" on December 16, 2021, researched by the Chen Wei research group of Zhejiang University School of Basic Medicine, joint with the Yin Weiwei research group of the School of Biophysics and the Lou Jizhong team of the Institute of Biophysics of the Chinese Academy of Sciences.Stimulatory immune receptor NKG2D binds diverse ligands to elicit differential anti-tumor and anti-virus immune responses. Two conflicting degeneracy recognition models based on static crystal structures and in-solution binding affinities have been considered for almost two decades. Whether and how NKG2D recognizes and discriminates diverse ligands remain unclear. Using live-cell based single-molecule biomechanical assay, we characterized the in situ binding kinetics of NKG2D interacting with different ligands in the absence or presence of mechanical force. We found that mechanical force application selectively prolonged NKG2D interaction lifetimes with the ligands MICA and MICB, but not with ULBPs, and that force-strengthened binding is much more pronounced for MICA than for other ligands. We also integrated steered molecular dynamics simulations and mutagenesis to reveal force-induced rotational conformational changes of MICA, involving formation of additional hydrogen bonds on its binding interface with NKG2D, impeding MICA dissociation under force. We further provided a kinetic triggering model to reveal that force-dependent affinity determines NKG2D ligand discrimination and its downstream NK cell activation. Together, our results demonstrate that NKG2D has a discrimination power to recognize different ligands, which depends on selective mechanical force-induced ligand conformational changes.