Abstract

Leukocytes in human bodies (such as T cell, naturalkiller (NK) cell, etc.) play key roles in screening cells infected by virus andsweeping 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’ accuratelydiscriminate, 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, thereexhibit specific markers on ‘invaders’, which can be discriminated by membranereceptors on ‘policemen’ with hypersensitivity. Thus, we focused on theunderlying mechanism of membrane receptors discriminating specific ligands, andpublished the research paper titled ‘NKG2D discriminates diverse ligandsthrough selectively mechano-regulated ligand conformational changes’ in theinternational professional academic journal "EMBO JOURNAL" onDecember 16, 2021, researched by the Chen Wei research group of ZhejiangUniversity School of Basic Medicine, joint with the Yin Weiwei research groupof the School of Biophysics and the Lou Jizhong team of the Institute ofBiophysics of the Chinese Academy of Sciences.Stimulatory immune receptor NKG2D binds diverseligands to elicit differential anti-tumor and anti-virus immune responses. Twoconflicting degeneracy recognition models based on static crystal structures andin-solution binding affinities have been considered for almost two decades.Whether and how NKG2D recognizes and discriminates diverse ligands remainunclear. Using live-cell based single-molecule biomechanical assay, wecharacterized the in situ binding kinetics of NKG2D interacting with differentligands in the absence or presence of mechanical force. We found thatmechanical force application selectively prolonged NKG2D interaction lifetimes withthe ligands MICA and MICB, but not with ULBPs, and that force-strengthenedbinding is much more pronounced for MICA than for other ligands. We also integratedsteered molecular dynamics simulations and mutagenesis to reveal force-inducedrotational conformational changes of MICA, involving formation of additional hydrogenbonds on its binding interface with NKG2D, impeding MICA dissociation underforce. We further provided a kinetic triggering model to reveal thatforce-dependent affinity determines NKG2D ligand discrimination and itsdownstream NK cell activation. Together, our results demonstrate that NKG2D hasa discrimination power to recognize different ligands, which depends onselective mechanical force-induced ligand conformational changes.