Lanz, A-L, Masi, G, Porciello, N et al. (13 more authors) (2021) Allosteric activation of T cell antigen receptor signaling by quaternary structure relaxation. Cell Reports, 36 (2). 109375. ISSN 2211-1247
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 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 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) |
Keywords: | adaptive immunity; allosteric mechanism; membrane signalling; molecular dynamics simulation; T cell activation; T cell antigen receptor |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Funding Information: | Funder Grant number Academy of Medical Sciences Not Known |
Depositing User: | Symplectic Publications |
Date Deposited: | 23 Jul 2021 14:40 |
Last Modified: | 21 Mar 2022 14:01 |
Status: | Published |
Publisher: | Cell Press |
Identification Number: | 10.1016/j.celrep.2021.109375 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:176171 |