Fig. 1: The molecular mechanism of how LAG3 inhibits TCR–CD3 signaling.
From: Sabotaging TCR signaling—LAG3 interferes with the CD3ε–LCK interaction
a In the resting state, CD3ε signaling motifs are not accessible for binding to LCK. Likewise, the BRS and FSALE motifs of LAG3 are shielded within the membrane. b Upon pMHC binding, the TCR–CD3 undergoes conformational changes, exposing the BRS and RK motifs, which then bind to LCK. TCR–CD3–LCK condensates form, allowing CD3 phosphorylation and downstream signaling. c Simultaneous binding to pMHCII brings TCR–CD3 into vicinity of LAG3 and induces KIEELE motif ubiquitination by CBL. Ubiquitination detaches the FSALE and EP motifs from the membrane allowing them to form condensates with CD3ε, thereby dissolving the CD3ε–LCK condensates. This inhibits TCR–CD3 signaling. Created with BioRender.com.
