Atomic-resolution view of complete TCR-CD3 revealed

Chai, Jijie

doi:10.1007/s13238-019-00677-7

Cited by 5 publications

(3 citation statements)

References 15 publications

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“…Even though the activation of TCR is an intricate process ( Chai, 2020 ; Dong et al, 2019 ; Mariuzza et al, 2020 ; Reinherz, 2019 ), significant progress has been made in understanding the conformational changes it entails. For example, in response to TCR engagement, the juxtamembrane domains of the ζζ homodimer have been experimentally reported to switch from a divaricated to a parallel conformation ( Lee et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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

Ye,

Morita,

Chang

et al. 2023

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

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

Ye,

Morita,

Chang

et al. 2023

eLife

View full text Add to dashboard Cite

show abstract

“…Even though the activation of TCR is an intricate process (Chai, 2020;Dong et al, 2019;Mariuzza et al, 2020;Reinherz, 2019), significant progress has been made to understand the conformational changes it entails. For example, in response to TCR engagement, the juxtamembrane domains of the ζζ homodimer have been experimentally reported to switch from a divaricated to a parallel conformation (Lee et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Allosteric Inhibition of the T Cell Receptor by a Designed Membrane Ligand

Morita

Groves

et al. 2022

Preprint

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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 bind 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 membrane ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit. As a result, in the presence of this Peptide Inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened in T cells. Co-localization and co-immunoprecipitation results in DIBMA native nanodiscs confirmed that PITCR was able to bind to the TCR. We propose that PITCR binds into a crevice present between the TM helices of the CD3ζ and CD3ϵ(δ) 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.

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“…Their potential role in any activation-induced conformational transitions can now be investigated with a precise structural rationale. The interfaces among TCR and CD3 components in the ECDs, while not the focus of this perspective, also provide structural context for the re-examination of an enormous number of prior biochemical, biophysical and modeling studies that are just beginning to be addressed in very recent reviews and commentaries. − …”

Section: Evaluation Of Experimental and Computational Tm Models Again...mentioning

confidence: 99%

Experimentally Guided Computational Methods Yield Highly Accurate Insights into Transmembrane Interactions within the T Cell Receptor Complex

et al. 2020

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Understanding how molecular interactions within the plasma membrane govern assembly, clustering, and conformational changes in single-pass transmembrane (TM) receptors has long presented substantial experimental challenges. Our previous work on activating immune receptors has combined direct biochemical and biophysical characterizations with both independent and experimentally restrained computational methods to provide novel insights into the key TM interactions underpinning assembly and stability of complex, multisubunit receptor systems. The recently published cryo-EM structure of the intact T cell receptor (TCR)-CD3 complex provides a unique opportunity to test the models and predictions arising from these studies, and we find that they are accurate, which we attribute to robust simulation environments and careful consideration of limitations related to studying TM interactions in isolation from additional receptor domains. With this in mind, we revisit results in other immune receptors and look forward to how similar methods may be applied to understand receptors for which little or no structural information is currently available.

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Atomic-resolution view of complete TCR-CD3 revealed

Cited by 5 publications

References 15 publications

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

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

Allosteric Inhibition of the T Cell Receptor by a Designed Membrane Ligand

Experimentally Guided Computational Methods Yield Highly Accurate Insights into Transmembrane Interactions within the T Cell Receptor Complex

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