Allosteric inhibition of the T cell receptor by a designed membrane ligand

The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypothese...

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Main Authors: Ye, Yujie, Morita, Shumpei, Chang, Justin J., Buckley, Patrick M., Wilhelm, Kiera B., DiMaio, Daniel, Groves, Jay T., Barrera, Francisco N.
Other Authors: Institute for Digital Molecular Analytics and Science (IDMxS)
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/173766
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1737662024-02-28T15:31:46Z Allosteric inhibition of the T cell receptor by a designed membrane ligand Ye, Yujie Morita, Shumpei Chang, Justin J. Buckley, Patrick M. Wilhelm, Kiera B. DiMaio, Daniel Groves, Jay T. Barrera, Francisco N. Institute for Digital Molecular Analytics and Science (IDMxS) Chemistry Ligands Phosphorylation The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease. Published version This work was supported by NIH grants R35GM140846 (to FNB) and R35CA242462 (to DD), and NIH training grant (T32AI055403) and National Science Foundation Predoctoral Fellowship (DGE-2139841) to PMB, and additionanlly by a Faculty-Graduate student award to YY (University of Tennessee). 2024-02-27T07:14:21Z 2024-02-27T07:14:21Z 2023 Journal Article Ye, Y., Morita, S., Chang, J. J., Buckley, P. M., Wilhelm, K. B., DiMaio, D., Groves, J. T. & Barrera, F. N. (2023). Allosteric inhibition of the T cell receptor by a designed membrane ligand. ELife, 12, e82861-. https://dx.doi.org/10.7554/eLife.82861 2050-084X https://hdl.handle.net/10356/173766 10.7554/eLife.82861 37796108 2-s2.0-85175587075 12 e82861 en DGE-2139841 R35CA242462 R35GM140846 T32AI055403 eLife © 2023 Ye et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Chemistry
Ligands
Phosphorylation
spellingShingle Chemistry
Ligands
Phosphorylation
Ye, Yujie
Morita, Shumpei
Chang, Justin J.
Buckley, Patrick M.
Wilhelm, Kiera B.
DiMaio, Daniel
Groves, Jay T.
Barrera, Francisco N.
Allosteric inhibition of the T cell receptor by a designed membrane ligand
description The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease.
author2 Institute for Digital Molecular Analytics and Science (IDMxS)
author_facet Institute for Digital Molecular Analytics and Science (IDMxS)
Ye, Yujie
Morita, Shumpei
Chang, Justin J.
Buckley, Patrick M.
Wilhelm, Kiera B.
DiMaio, Daniel
Groves, Jay T.
Barrera, Francisco N.
format Article
author Ye, Yujie
Morita, Shumpei
Chang, Justin J.
Buckley, Patrick M.
Wilhelm, Kiera B.
DiMaio, Daniel
Groves, Jay T.
Barrera, Francisco N.
author_sort Ye, Yujie
title Allosteric inhibition of the T cell receptor by a designed membrane ligand
title_short Allosteric inhibition of the T cell receptor by a designed membrane ligand
title_full Allosteric inhibition of the T cell receptor by a designed membrane ligand
title_fullStr Allosteric inhibition of the T cell receptor by a designed membrane ligand
title_full_unstemmed Allosteric inhibition of the T cell receptor by a designed membrane ligand
title_sort allosteric inhibition of the t cell receptor by a designed membrane ligand
publishDate 2024
url https://hdl.handle.net/10356/173766
_version_ 1794549347887611904