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Lanz, Anna-Lisa; Masi, Giulia; Porciello, Nicla; Cohnen, Andre; Cipria, Deborah; Prakaash, Dheeraj; Balint, Stefan; Raggiaschi, Roberto; Galgano, Donatella; Cole, David K.; Lepore, Marco; Dushek, Omer; Dustin, Michael L.; Sansom, Mark S. P.; Kalli, Antreas C. and Acuto, Oreste (2021): Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation. In: Cell Reports, Vol. 36, No. 2, 109375

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The mechanismof T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCR beta or CD3 zeta that augment peptide T cell antigen receptor (pMHC)-induced signaling not explicable by enhanced ligand binding, lateral diffusion, clustering, or co-receptor function. Using a biochemical assay and molecular dynamics simulation, we demonstrate that the gain-of-function mutations loosen the interaction between TCR alpha beta and CD3 zeta. Similar to the activating mutations, pMHC binding reduces TCR alpha beta cohesion with CD3 zeta. This event occurs prior to CD3 zeta phosphorylation and at 0 degrees C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCR alpha beta cohesion with CD3 zeta in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCR alpha beta to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3 zeta phosphorylation and initiate signal propagation.

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