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, D.K.; Lepore, Marco; Dushek, Omer; Dustin, Michael L.; Sansom, Mark S. P.; Kalli, Antreas C.; Acuto, Oreste

doi:10.1016/j.celrep.2021.109375

Cited by 26 publications

(43 citation statements)

References 102 publications

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“…Therefore, an allostery-based stimulation of conformational changes in the TCR-CD3 which alters the interactions of zz TMR with the rest of the TCR-CD3 as seen in our simulations can potentially contribute to the unbinding of zz CYRs from CD3 CYRs and further increase the exposure of their ITAMs for phosphorylation. This PLOS COMPUTATIONAL BIOLOGY mechanism is consistent with our recent data suggesting that TCR engagement with pMHC leads to zz loosening relative to the rest of the complex [20]. Our simulations suggest that the TCR-CD3 CYRs undergo coiling, thereby not allowing all ITAM tyrosines to penetrate the membrane.…”

Section: Discussionsupporting

confidence: 90%

“…Our simulations suggested an alteration in the TMR configuration where the zz and CD3δε dimers lost contact thereby bringing CD3δ and TCRβ TMRs closer than observed in the cryo-EM structure. Moreover, we identified possible conformations of the TCR-CD3 ECD and interactions of VαVβ with CD3 ECDs indicating flexibility of the antigen-binding domain of the TCRαβ, in line with studies that identified allosteric sites in the TCRαβ constant domains [2,20,[28][29][30][31].…”

Section: Discussionsupporting

confidence: 81%

“…This dissociation allows augmented ITAM access by active LCK [13] followed by sustained ITAM phosphorylation leading to activation of ZAP-70 to propagate intracellular signalling [7]. Recent data suggest that allosterically-induced conformational changes triggered by pMHC binding to TCR-CD3 facilitate ITAM exposure [20]. It has also been proposed that the dissociation of CYRs could occur by ITAM phosphorylation due to an increase in their net electronegative charge.…”

Section: Discussionmentioning

confidence: 99%

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Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

et al. 2021

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The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

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Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

et al. 2021

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“…The phosphorylation step acts as a threshold for the activation of T-cell signaling. In the basal state, the tyrosine residues in the cytosolic domain of the CD3 chain are embedded in the lipid bilayer, making them inaccessible for phosphorylation by Lck [ 163–165 ]. The binding of pMHC to the TCR reorients the cytosolic domain of the CD3 chain dislodging the tyrosine residues from the membrane allowing the UD of Lck to interact.…”

Section: Regulation Of Lck Activationmentioning

confidence: 99%

Regulating the discriminatory response to antigen by T-cell receptor

et al. 2022

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The cell-mediated immune response constitutes a robust host defense mechanism to eliminate pathogens and oncogenic cells. T-cells play a central role in such a defense mechanism and creating memories to prevent any potential infection. T-cell recognizes foreign antigen by its surface receptors when presented through antigen-presenting cells and calibrates its cellular response by a network of intracellular signaling events. Activation of T-cell receptor (TCR) leads to changes in gene expression and metabolic networks regulating cell development, proliferation, and migration. TCR does not possess any catalytic activity, and the signaling initiates with the colocalization of several enzymes and scaffold proteins. Deregulation of T cell signaling is often linked to autoimmune disorders like SCID, Rheumatoid arthritis, and multiple sclerosis. The TCR remarkably distinguishes the minor difference between self and non-self antigen through a kinetic proofreading mechanism. The output of TCR signaling is determined by the half-life of the receptor-antigen complex and the time taken to recruit and activate the downstream enzymes. A longer half-life of a non-self antigen receptor complex could initiate downstream signaling by activating associated enzymes. Whereas, the short-lived self-peptide receptor complex disassembles before the downstream enzymes are activated. Activation of TCR rewires the cellular metabolic response to aerobic glycolysis from oxidative phosphorylation. How does the early event in the TCR signaling cross-talk with the cellular metabolism is an open question. In this review, we have discussed the recent developments in understanding the regulation of TCR signaling, and then we reviewed the emerging role of metabolism in regulating T-cell function.

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“…Activation of T cells is triggered by the engagement of the T cell receptor (TCR) with antigenic peptides presented by major histocompatibility complexes (pMHC) (Courtney, Lo, & Weiss, 2018;Mariuzza, Agnihotri, & Orban, 2019) . Upon pMHC binding, allosteric sites in the extracellular and transmembrane regions of the T cell receptor-CD3 complex (TCR-CD3) (He et al, 2020;Lanz et al, 2021) promote exposure of immunoreceptor tyrosine-based activation motifs (ITAMs) in the cytoplasmic tails of CD3/z subunits. Further, ITAMs are promptly phosphorylated by Lck.…”

Section: Introductionmentioning

confidence: 99%

Molecular dynamics simulations reveal membrane lipid interactions of the full-length lymphocyte specific kinase Lck

Prakaash

Cook

Acuto

et al. 2022

Preprint

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The membrane-bound lymphocyte-specific protein-tyrosine kinase (Lck) triggers T cell antigen receptor signalling to initiate adaptive immune responses. Despite many structure-function studies, the mode of action of Lck and the potential role of plasma membrane lipids in regulating Lck’s activity remains elusive. Advances in molecular dynamics simulations of membrane proteins in complex lipid bilayers have opened a new perspective in gathering such information. Here, we have modelled the full-length Lck open and closed conformations available from crystallographic studies and simulated its interaction with the inner leaflet of the T cell plasma membrane. In both conformations, we found that the unstructured unique domain and the structured domains including the kinase interacted with the membrane with a preference for PIP lipids. Interestingly, our simulations suggest that the Lck-SH2 domain interacts with lipids differently in the open and closed Lck conformations, demonstrating that lipid interaction can potentially regulate Lck’s conformation and in turn modulate T cell signalling. Additionally, the Lck-SH2 and kinase domain residues that significantly contacted PIP lipids are found to be conserved among the Src family of kinases, thereby potentially representing similar PIP interactions within the family.

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

Cited by 26 publications

References 102 publications

Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region

Regulating the discriminatory response to antigen by T-cell receptor

Molecular dynamics simulations reveal membrane lipid interactions of the full-length lymphocyte specific kinase Lck

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