Panel A: LCK cycles among active, primed, and inactive conformations when bound to CD4 or free. CD45 dephosphorylates Y505 to promote activation, while CSK phosphorylates Y505 to maintain the inactive state. Autophosphorylation of Y394 stabilizes the active conformation. Zn2 positive coordinates LCK binding to CD4 slash CD8 coreceptors. Panel B: Upon TCR engagement, free active LCK phosphorylates ITAMs within CD3 chains, initiating TCR signaling. Co-receptor-bound LCK modulates signaling sensitivity and efficiency. ITAM phosphorylation enables ZAP-70 recruitment and activation of downstream effectors including LAT, SLP-76, and ITK.
Regulation and signaling functions of LCK in proximal TCR signaling. (A) LCK exists in co-receptor–bound and free pools, each cycling among active, primed, and inactive conformations. CD45 dephosphorylates the inhibitory Y505, promoting activation, whereas CSK (recruited via PAG) phosphorylates Y505 to maintain the inactive state. Autophosphorylation of Y394 stabilizes the active conformation. Zn2+ coordinates LCK binding to CD4/CD8 co-receptors. (B) Upon TCR engagement, the free, active pool of LCK initiates TCR signaling via phosphorylation of ITAMs within CD3 chains, while co-receptor–bound LCK modulates sensitivity, efficiency, and lineage calibration. ITAM phosphorylation enables ZAP-70 recruitment and activation of downstream effectors, including LAT, SLP-76, and ITK.