Mechanical force regulates ligand binding and function of PD-1.

Autor: Li K; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA.; Shennon Biotechnologies, San Francisco, CA, USA., Cardenas-Lizana P; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA.; Department of Bioengineering and Chemical Engineering, University of Engineering and Technology-UTEC, Lima, Peru., Lyu J; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA.; L.E.K. consulting, Boston, MA, USA., Kellner AV; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Elephas, Madison, WI, USA., Li M; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA., Cong P; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA., Watson VE; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA., Yuan Z; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA.; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.; Alfred E. Mann Department of Biomedical Engineering, University of Southern California, Los Angeles, CA, USA., Ahn E; Emory Vaccine Center, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA.; Merck, South San Francisco, CA, USA., Doudy L; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA., Li Z; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.; School of Mechanics and Engineering Science, Shanghai University, Shanghai, China., Salaita K; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA.; Department of Chemistry, Emory University, Atlanta, GA, 30322, USA., Ahmed R; Emory Vaccine Center, Atlanta, GA, USA.; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA., Zhu C; Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA, USA. cheng.zhu@bme.gatech.edu.; Parker H. Petit Institute for Bioengineering and Biosciences, Atlanta, GA, USA. cheng.zhu@bme.gatech.edu.; George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA. cheng.zhu@bme.gatech.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 27; Vol. 15 (1), pp. 8339. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1038/s41467-024-52565-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: