The allostery model of TCR regulation
Schamel WW, Alarcon B, Höfer T, Minguet S
In BIOSS publication we review the evidences that the T cell antigen receptor (TCR) is regulated by conformational switches. From this we develop an allostery model of the regulation of the TCR’s activity. In the resting conformation, the TCR is not phosphorylated and is inactive. Binding of its ligand stabilizes the active conformation, leading to TCR phosphorylation and signaling. In heterotropic allostery the ligand and membrane cholesterol serve opposing functions as positive and negative allosteric regulators, respectively. In resting T cells cholesterol keeps TCRs in the resting conformation that otherwise would become spontaneously active. This regulation is well described by the Monod-Wyman-Changeux model of allostery. For a number of membrane proteins BIOSS esearchers have shown that they are expressed as pre-clustered assemblies, called nanoclusters. This is also the case for the TCR and might allow for homotropic allostery, in which individual TCRs could positively cooperate and thus enhance the sensitivity of T cell activation.
