The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Abstract The αβ T‐cell receptor (TCR) is a multiprotein complex controlling the activation of T cells. Although the structure of the complete TCR is not known, cumulative evidence supports that the TCR cycles between different conformational states that are promoted either by thermal motion or by force. These structural transitions determine whether the TCR engages intracellular effectors or not, regulating TCR phosphorylation and signaling. As for other membrane receptors, ligand binding selects and stabilizes the TCR in active conformations, and/or switches the TCR to activating states that were not visited before ligand engagement. Here we review the main models of TCR allostery, that is, ligand binding at TCRαβ changes the structure at CD3 and ζ. (a) The ITAM and proline‐rich sequence exposure model, in which the TCR's cytoplasmic tails shield each other and ligand binding exposes them for phosphorylation. (b) The membrane‐ITAM model, in which the CD3ε and ζ tails are sequestered inside the membrane and again ligand binding exposes them. (c) The mechanosensor model in which ligand binding exerts force on the TCR, inducing structural changes that allow signaling. Since these models are complementary rather than competing, we propose a unified model that aims to incorporate all existing data.