Mechanical force regulates ligand binding and function of PD-1

doi:10.1038/s41467-024-52565-2

Mechanical force regulates ligand binding and function of PD-1

2024-09-27

0

OA

AI

DOI：10.1038/s41467-024-52565-2

Original

Save

View PDF

Abstract

En 中文

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.

Keywords:

T-CELL-ACTIVATION

MOLECULAR-DYNAMICS

DEATH-1 PD-1

IN-SITU

RECEPTOR

COMPLEX

KINETICS

TCR

ACCUMULATION

EXPRESSION

Mechanical force regulates ligand binding and function of PD-1

Abstract

AI Summary

Journal

Organization