Mechanical force regulates ligand binding and function of PD-1
- PMID: 39333505
- PMCID: PMC11437077
- DOI: 10.1038/s41467-024-52565-2
Mechanical force regulates ligand binding and function of PD-1
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 <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).
Conflict of interest statement
The authors declare no competing interests.
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Update of
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Mechanical force regulates ligand binding and function of PD-1.bioRxiv [Preprint]. 2023 Aug 15:2023.08.13.553152. doi: 10.1101/2023.08.13.553152. bioRxiv. 2023. Update in: Nat Commun. 2024 Sep 27;15(1):8339. doi: 10.1038/s41467-024-52565-2. PMID: 37645980 Free PMC article. Updated. Preprint.
References
-
- Barber, D. L. et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature439, 682–687 (2006). - PubMed
-
- Day, C. L. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature443, 350–354 (2006). - PubMed
-
- Jin, H. T., Ahmed, R. & Okazaki, T. Role of PD-1 in regulating T-cell immunity. Curr. Top. Microbiol. Immunol.350, 17–37 (2011). - PubMed
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