Mechanical force regulates ligand binding and function of PD-1

Kaitao Li, Paul Cardenas-Lizana, Jintian Lyu, Anna V. Kellner, Menglan Li, Peiwen Cong, Valencia E. Watson, Zhou Yuan, Eunseon Ahn, Larissa Doudy, Zhenhai Li, Khalid Salaita, Rafi Ahmed and Cheng Zhu ()
Additional contact information
Kaitao Li: Wallace H. Coulter Department of Biomedical Engineering
Paul Cardenas-Lizana: Wallace H. Coulter Department of Biomedical Engineering
Jintian Lyu: Wallace H. Coulter Department of Biomedical Engineering
Anna V. Kellner: Wallace H. Coulter Department of Biomedical Engineering
Menglan Li: Wallace H. Coulter Department of Biomedical Engineering
Peiwen Cong: Wallace H. Coulter Department of Biomedical Engineering
Valencia E. Watson: Wallace H. Coulter Department of Biomedical Engineering
Zhou Yuan: Wallace H. Coulter Department of Biomedical Engineering
Eunseon Ahn: Emory Vaccine Center
Larissa Doudy: Wallace H. Coulter Department of Biomedical Engineering
Zhenhai Li: Wallace H. Coulter Department of Biomedical Engineering
Khalid Salaita: Wallace H. Coulter Department of Biomedical Engineering
Rafi Ahmed: Emory Vaccine Center
Cheng Zhu: Wallace H. Coulter Department of Biomedical Engineering

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract 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 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.

Date: 2024
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DOI: 10.1038/s41467-024-52565-2

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