Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation

Lanz, Anna-Lisa, Masi, Giulia, Porciello, Nicla, Cohnen, André, Cipria, Deborah, Prakaash, Dheeraj, Bálint, Štefan, Raggiaschi, Roberto, Galgano, Donatella, Cole, David K. ORCID: https://orcid.org/0000-0003-0028-9396, 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. Cell Reports 36 (2) , 109375. 10.1016/j.celrep.2021.109375

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Abstract

The mechanism of T cell antigen receptor (TCR-CD3) signaling remains elusive. Here, we identify mutations in the transmembrane region of TCRβ or CD3ζ that augment peptide-major histocompatibility complex (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 TCRαβ and CD3ζ. Similar to the activating mutations, pMHC binding reduces TCRαβ cohesion with CD3ζ. This event occurs prior to CD3ζ phosphorylation and at 0°C. Moreover, we demonstrate that soluble monovalent pMHC alone induces signaling and reduces TCRαβ cohesion with CD3ζ in membrane-bound or solubilised TCR-CD3. Our data provide compelling evidence that pMHC binding suffices to activate allosteric changes propagating from TCRαβ to the CD3 subunits, reconfiguring interchain transmembrane region interactions. These dynamic modifications could change the arrangement of TCR-CD3 boundary lipids to license CD3ζ phosphorylation and initiate signal propagation.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Cell Press
ISSN:	2211-1247
Date of First Compliant Deposit:	9 February 2022
Date of Acceptance:	18 June 2021
Last Modified:	11 May 2023 12:41
URI:	https://orca.cardiff.ac.uk/id/eprint/147344

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