Mechanical force regulates ligand binding and function of PD-1

Li K.; Cardenas-Lizana P.; Lyu J.; Kellner A.V.; Li M.; Cong P.; Watson V.E.; Yuan Z.; Ahn E.; Doudy L.; Li Z.; Salaita K.; Ahmed R.; Zhu C. · Nature Communications (2024) · DOI: 10.1038/s41467-024-52565-2

Resumen

Despite the success of PD-1 blockade in cancer therapy, how PD-1 initiates signaling remains unclear. Soluble PD-L1 is found in patient sera and can bind PD-1 but fails to suppress T cell function. Here, we show that PD-1 function is reduced when mechanical support on ligand is removed. Mechanistically, cells exert forces to PD-1 and prolong bond lifetime at forces <7 pN (catch bond) while accelerate dissociation at forces >8pN (slip bond). Molecular dynamics of PD-1–PD-L2 complex suggests force may cause relative rotation and translation between the two molecules yielding distinct atomic contacts not observed in the crystal structure. Compared to wild-type, PD-1 mutants targeting the force-induced distinct interactions maintain the same binding affinity but suppressed/eliminated catch bond, lowered rupture force, and reduced inhibitory function. Our results uncover a mechanism for cells to probe the mechanical support of PD-1–PD-Ligand bonds using endogenous forces to regulate PD-1 signaling. © The Author(s) 2024.

Instituciones: Universidad de Ingeniería y Tecnología