T cell receptors are structures capable of initiating signaling in the absence of large conformational rearrangements
Fernandes RA, Shore DA, Vuong MT, Yu C, Zhu X, Pereira-Lopes S, Brouwer H, Fennelly JA, Jessup CM, Evans EJ, Wilson IA, Davis SJ. (2012), J Biol Chem. 287, 13324-35
Native and non-native ligands of the T cell receptor (TCR), including antibodies, have been proposed to induce signaling in T cells via intra- or intersubunit conformational rearrangements within the extracellular regions of TCR complexes. We have investigated whether any signatures can be found for such postulated structural changes during TCR triggering induced by antibodies, using crystallographic and mutagenesis-based approaches. The crystal structure of murine CD3ε complexed with the mitogenic anti-CD3ε antibody 2C11 enabled the first direct structural comparisons of antibody-liganded and unliganded forms of CD3ε from a single species, which revealed that antibody binding does not induce any substantial rearrangements within CD3ε. Saturation mutagenesis of surface-exposed CD3ε residues, coupled with assays of antibody-induced signaling by the mutated complexes, suggests a new configuration for the complex within which CD3ε is highly exposed and reveals that no large new CD3ε interfaces are required to form during antibody-induced signaling. The TCR complex therefore appears to be a structure that is capable of initiating intracellular signaling in T cells without substantial structural rearrangements within or between the component subunits. Our findings raise the possibility that signaling by native ligands might also be initiated in the absence of large structural rearrangements in the receptor.
Key figure: Surface mutation of TCRαβ and model for the TCR-CD3 complex
A, three views of the surface of the TCRαβ heterodimer (from Protein Data Bank code 1OGA (71)), each related by a 120° rotation about the vertical axis. The α chain is colored blue-gray, and the β chain is yellow. Mutated residues are colored according to whether their mutation reduces TCR expression by more than 85% (red), by 60–85% (orange), or by less than 60% (green) versus wild-type TCR expression. B, cartoon illustration of the proposed quaternary arrangement of extracellular domains within the TCR-CD3 complex based on all of the mutagenesis data presented here. It remains unclear whether both CD3γ and δ contact the TCRαβ heterodimer or whether one (most likely CD3δ (17)) forms the major contact and stabilizes the association of the other in the complex in the absence of direct contacts with TCRαβ. See also supplemental Figs. S5 and S6.