Mechanical force regulates ligand binding and function of PD-1

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.

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Publication Details

Journal
Nature Communications
Published
2024-09-27
DOI
https://doi.org/10.1038/s41467-024-52565-2
Citations
14
Primary Topic
Cellular Mechanics and Interactions
Type
article
Field-Weighted Citation Impact
4.24

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article

Mechanical force regulates ligand binding and function of PD-1

Peiwen Cong, Kaitao Li, Larissa Doudy, Rafi Ahmed et al.
14 citations
Nature Communications
Cellular Mechanics and Interactions
4.24
article

Mechanical force regulates ligand binding and function of PD-1

Peiwen Cong, Kaitao Li, Larissa Doudy, Rafi Ahmed, Khalid Salaita, Eunseon Ahn, Cheng Zhu, Menglan Li, Anna Kellner, Jintian Lyu, Paul Cárdenas-Lizana, Zhou Yuan, Valencia Watson, Zhenhai Li
article en
14 citations

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.

Nature CommunicationsVol. 15(1)
Shanghai University (CN), University of Southern California (US), Merck & Co., Inc., Rahway, NJ, USA (United States) (US), Georgia Institute of Technology (US), Emory Healthcare (US), Emory University (US), The Wallace H. Coulter Department of Biomedical Engineering (US), Raptamer Discovery Group (United States) (US), LEK Consulting (United States) (US), Universidad de Ingeniería y Tecnología (PE), Bioengineering Center (RU)
National Science Foundation, National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 5%
Cellular Mechanics and Interactions
4.24
DOIOpen Access PDFOpenAlex
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