The short length of the extracellular domain of zeta is crucial for T cell antigen receptor function.

The T cell antigen receptor (TCR-CD3) consists of the pMHC-binding TCRalphabeta heterodimer and the signalling dimers CD3deltaepsilon, CD3gammaepsilon and zetazeta. The very short length of the extracellular domain (EC) of the zeta chain is preserved through evolution, however a rational explanation for this observation has not been elucidated. Here, we show that TCR-CD3 assembly is clearly defective when the murine zeta EC domain is artificially enlarged. Under these conditions, the TCR-CD3 complex is super-competent in transducing activation signals upon engagement. Furthermore, the TCR-CD3 complexes containing enlarged zeta EC domains underwent ligand-induced conformation changes with higher efficiency than TCR-CD3 complexes with an unmodified zeta EC domain. Together these data suggest that a short zeta EC domain is needed to correctly assemble the TCR-CD3 complex. When this domain is enlarged, the resulting TCR-CD3 complex is distorted leading to a hyperactive phenotype and enhanced T cell activation.