The inhibitory receptor programmed cell death protein 1 (PD-1) suppresses T cell activation primarily by recruiting the src homology 2 domain-containing phosphatase 2 (SHP2), thereby unleashing its phosphatase activity. However, a purely enzymatic model struggles to fully explain the rapid and robust disruption of proximal T cell receptor (TCR) and CD28 signaling. Here, by integrating X-ray crystallography, single-molecule magnetic tweezers, supported lipid bilayers, TIRF imaging, liquid-liquid phase separation, and cellular assays, we uncover a dual-layered inhibitory mechanism of the PD-1/SHP2 axis. Mechanistically, we determine the crystal structure of SHP2 in complex with dually phosphorylated PD-1 cytoplasmic motifs (pPD-1), revealing a ligand-induced open conformation, which is distinct from the oncogenic E76K-associated state. We further directly resolve the closed-to-open conformational dynamics of individual SHP2 molecules, characterized by an 8-nm transition amplitude, and demonstrate that pPD-1 accelerates the transition by at least 94-fold. Crucially, the pPD-1-mediated highly open conformation exposes the tandem SH2 (t-SH2) domains to function as a biophysical barrier. Independent of phosphatase activity, these domains directly dismantle pTCR and pCD28 signaling condensates to suppress T cell activation. Together, our findings establish a model in which pPD-1 remodels SHP2 structural dynamics and drives a non-catalytic inhibitory mechanism of TCR and CD28 signaling, suggesting next-generation immunotherapy design to reverse T cell suppression.
Fei, P., Jiao, P., Gao, J., Chen, H., Zhang, Y., Chen, L., Wu, P., Chen, L., Valvo, S., Dustin, M. L., Lou, J., Zhou, C., Chen, W.
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