Molecular Modelling and Endoplasmic Reticulum Retention of Mutated TCR/CD3 Complexes

T cell receptor (TCR)/CD3 complex assembly takes place in the endoplasmic reticulum (ER). Normal TCR/CD3 complexes egress from the ER to the cis‐Golgi, where the interaction with ζ2 homodimers occurs. This interaction leads to further uncontrolled transport of TCR/CD3/ζ molecules to the cell surface. The purpose of the present experiments was to determine firstly the basis for the impact of the phe195/216 = > val mutations on TCR/CD3 expression in Jurkat cells, and secondly why mutated J79‐cell TCRαβ/CD3 hexamers are prevented from interacting with ζ2 homodimers. We found that phe = > val mutations cause serious perturbations in a so far undefined hydrophobic area formed by the two phe195/216 on β‐strand F and aromatic/large hydrophobic amino acids on neighboring β‐strands B and A in Cα and Cβ domains, respectively. In addition, TCR/CD3 hexamers and ζ2 homodimers colocalize in normal Jurkat T cells, in revertant J79r58 cells, and in J79 cells transfected with wild‐type TCRα cDNA but not in J79 mutant cells (confocal microscopy). Furthermore, mutated TCR/CD3 complexes seem to be actively retained in the ER in J79 cells but not in revertant J79r58 cells by a nondominant mechanism. We propose that a hitherto undefined ER‐retention molecule controls both the protein structure and egress of TCR/CD3 complexes from the ER of αβ and γδ T cells.