Structural Model of the Extracellular Assembly of the TCR-CD3 Complex

Natarajan, Aswin; Nadarajah, Vidushan; Felsövályi, Klára; Wang, Wenjuan; Jeyachandran, Vivian R.; Wasson, Riley A.; Cardozo, Timothy; Bracken, Clay; Krogsgaard, Michelle

doi:10.1016/j.celrep.2016.02.081

Cited by 48 publications

(108 citation statements)

References 60 publications

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“…It is therefore conceivable that dynamically driven p/MHC-induced allosteric changes in the constant regions of the TCR, supported both by NMR data presented here and previous hydrogen/deuterium exchange experiments45, could potentiate interactions with CD3γɛ and δɛ, which, according to recent NMR studies, interact only weakly with the free TCR2526.…”

Section: Discussionsupporting

confidence: 74%

“…Early NMR studies found the interaction of CD3δɛ with TCR in solution too weak to detect significant chemical shift perturbations41. More recent work found that only a mixture of CD3γɛ and CD3δɛ subunits produced detectable effects on the H3 and H4 helices of the TCR Cβ25, while a subsequent study reported weak but measurable perturbations in both Cα and Cβ upon addition of CD3δɛ or CD3γɛ, respectively26. On the cytoplasmic side, NMR studies have revealed lipid-sensitive conformational changes in the signalling domains of the CD3ζζ homodimer42 and the CD3ɛ subunit38.…”

Section: Discussionmentioning

confidence: 99%

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An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role

et al. 2017

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The molecular mechanism through which the interaction of a clonotypic αβ T-cell receptor (TCR) with a peptide-loaded major histocompatibility complex (p/MHC) leads to T-cell activation is not yet fully understood. Here we exploit a high-affinity TCR (B4.2.3) to examine the structural changes that accompany binding to its p/MHC ligand (P18-I10/H2-Dd). In addition to conformational changes in complementarity-determining regions (CDRs) of the TCR seen in comparison of unliganded and bound X-ray structures, NMR characterization of the TCR β-chain dynamics reveals significant chemical shift effects in sites removed from the MHC-binding site. Remodelling of electrostatic interactions near the Cβ H3 helix at the membrane-proximal face of the TCR, a region implicated in interactions with the CD3 co-receptor, suggests a possible role for an allosteric mechanism in TCR signalling. The contribution of these TCR residues to signal transduction is supported by mutagenesis and T-cell functional assays.

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Section: Discussionsupporting

confidence: 74%

Section: Discussionmentioning

confidence: 99%

An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role

et al. 2017

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“…These regions include the TCRα AB loop, the TCRβ FG loop, the TCRβ helix 3, and the stalk regions of CD3 . These regions are presumably involved in the interaction of TCRαβ with CD3 and they are not reported to bind to any other protein. Therefore, these mutations hinder the transmission of proper conformational arrangements between the different modules of the TCR, preventing that the TCR adopts the optimal conformation for being triggered.…”

Section: Tcr Triggering Modelsmentioning

confidence: 99%

“…Deuterium/hydrogen exchange and NMR data have shown that the TCRαβ V and C regions are flexible. Upon pMHC binding this flexibility is reduced, and regions implicated in communication with CD3 show large structural changes. These are the Cα AB and the Cβ FG loops, residues near the Cβ αA helix and the Cβ H3 and H4 helices (Figure ).…”

Section: Ligand‐regulated Changes In the Tcr Ectodomainsmentioning

confidence: 99%

The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Schamel

Alarcón

Minguet

2019

Immunological Reviews

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The αβ T‐cell receptor (TCR) is a multiprotein complex controlling the activation of T cells. Although the structure of the complete TCR is not known, cumulative evidence supports that the TCR cycles between different conformational states that are promoted either by thermal motion or by force. These structural transitions determine whether the TCR engages intracellular effectors or not, regulating TCR phosphorylation and signaling. As for other membrane receptors, ligand binding selects and stabilizes the TCR in active conformations, and/or switches the TCR to activating states that were not visited before ligand engagement. Here we review the main models of TCR allostery, that is, ligand binding at TCRαβ changes the structure at CD3 and ζ. (a) The ITAM and proline‐rich sequence exposure model, in which the TCR's cytoplasmic tails shield each other and ligand binding exposes them for phosphorylation. (b) The membrane‐ITAM model, in which the CD3ε and ζ tails are sequestered inside the membrane and again ligand binding exposes them. (c) The mechanosensor model in which ligand binding exerts force on the TCR, inducing structural changes that allow signaling. Since these models are complementary rather than competing, we propose a unified model that aims to incorporate all existing data.

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“…More recently, NMR characterization of the ␤ chain of a mouse TCR (B4.2.3) specific for an HIV-1 gp120-derived peptide bound to a mouse MHC class I molecule (H2-D d ) revealed amide resonance changes in C␤ upon pMHC ligation (29). Some of these changes were near constant ␤ domain (C␤) residues previously implicated by NMR to interact with CD3 (30,31). Here, we report NMR characterization and molecular dynamics (MD) simulations of both the ␣ and ␤ chains of a human antiviral TCR (A6) that recognizes the Tax antigen (LLFGYPVYV) from human T cell lymphotropic virus-1 (HTLV-1) bound to the human MHC class I molecule HLA-A2 (32).…”

mentioning

confidence: 97%

Peptide–MHC (pMHC) binding to a human antiviral T cell receptor induces long-range allosteric communication between pMHC- and CD3-binding sites

Rangarajan¹,

He²,

Chen³

et al. 2018

Journal of Biological Chemistry

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T cells generate adaptive immune responses mediated by the T cell receptor (TCR)-CD3 complex comprising an αβ TCR heterodimer noncovalently associated with three CD3 dimers. In early T cell activation, αβ TCR engagement by peptide-major histocompatibility complex (pMHC) is first communicated to the CD3 signaling apparatus of the TCR-CD3 complex, but the underlying mechanism is incompletely understood. It is possible that pMHC binding induces allosteric changes in TCR conformation or dynamics that are then relayed to CD3. Here, we carried out NMR analysis and molecular dynamics (MD) simulations of both the α and β chains of a human antiviral TCR (A6) that recognizes the Tax antigen from human T cell lymphotropic virus-1 bound to the MHC class I molecule HLA-A2. We observed pMHC-induced NMR signal perturbations in the TCR variable (V) domains that propagated to three distinct sites in the constant (C) domains: 1) the Cβ FG loop projecting from the Vβ/Cβ interface; 2) a cluster of Cβ residues near the Cβ αA helix, a region involved in interactions with CD3; and 3) the Cα AB loop at the membrane-proximal base of the TCR. A biological role for each of these allosteric sites is supported by previous mutational and functional studies of TCR signaling. Moreover, the pattern of long-range, ligand-induced changes in TCR A6 revealed by NMR was broadly similar to that predicted by the MD simulations. We propose that the unique structure of the TCR β chain enables allosteric communication between the TCR-binding sites for pMHC and CD3.

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Structural Model of the Extracellular Assembly of the TCR-CD3 Complex

Cited by 48 publications

References 60 publications

An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role

An allosteric site in the T-cell receptor Cβ domain plays a critical signalling role

The TCR is an allosterically regulated macromolecular machinery changing its conformation while working

Peptide–MHC (pMHC) binding to a human antiviral T cell receptor induces long-range allosteric communication between pMHC- and CD3-binding sites

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