A di-glycine motif in the cytoplasmic tail of CD3ε required for transmission of allosteric changes in the TCR and full CD3ζ phosphorylation
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How the T cell receptor (TCR) recognizes its antigen ligand and transmits this information to the cytoplasm for T cell activation is still a matter of debate. A large body of experimental data suggests that the TCR undergoes allosteric changes upon ligand binding that are responsible for the outside-in transfer of information. One of the hallmarks of TCR allostery is the induced exposure of a proline-rich sequence (PRS) in the cytoplasmic tail of the CD3ε subunit, enabling binding to the cytoplasmic adaptor protein Nck. We show here that a glycine-to-alanine mutation (G169A) in a conserved di-glycine motif upstream of the PRS impairs TCR binding to Nck upon stimulation with an activating antibody. Furthermore, the mutation hinders CD3ε tyrosine phosphorylation and, interestingly, selectively affects CD3ζ subunit phosphorylation at Tyr83. In addition, the G169A mutation impairs the phosphorylation of Lck at Ser59. Taken together, these data support the concept of TCR allostery and highlight the existence of a regulated sequence of interactions between TCR subunits and associated effector proteins.
