Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions

Chavent, Matthieu; Seiradake, E.; Jones, E Y; Sansom, Mark S. P.

doi:10.1016/j.str.2015.11.008

Cited by 34 publications

(42 citation statements)

References 78 publications

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“…Allosteric transmission of biological signals over long distances has now been documented for numerous proteins (54), including cell-surface receptors such as the EphA2 receptor (55). Like mechanosensing, TCR allostery could explain the exceptional ability of a single pMHC molecule binding to an exclusively monomeric TCR to initiate T-cell signaling without any requirement for ligand-induced receptor oligomerization (6) and before formation of the immunological synapse (56).…”

Section: Arguments For and Against Tcr Allosterymentioning

confidence: 99%

The structural basis of T-cell receptor (TCR) activation: An enduring enigma

2019

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T cells are critical for protective immune responses to pathogens and tumors. The T-cell receptor (TCR)–CD3 complex is composed of a diverse αβ TCR heterodimer noncovalently associated with the invariant CD3 dimers CD3ϵγ, CD3ϵδ, and CD3ζζ. The TCR mediates recognition of antigenic peptides bound to MHC molecules (pMHC), whereas the CD3 molecules transduce activation signals to the T cell. Whereas much is known about downstream T-cell signaling pathways, the mechanism whereby TCR engagement by pMHC is first communicated to the CD3 signaling apparatus, a process termed early T-cell activation, remains largely a mystery. In this review, we examine the molecular basis for TCR activation in light of the recently determined cryoEM structure of a complete TCR–CD3 complex. This structure provides an unprecedented opportunity to assess various signaling models that have been proposed for the TCR. We review evidence from single-molecule and structural studies for force-induced conformational changes in the TCR–CD3 complex, for dynamically-driven TCR allostery, and for pMHC-induced structural changes in the transmembrane and cytoplasmic regions of CD3 subunits. We identify major knowledge gaps that must be filled in order to arrive at a comprehensive model of TCR activation that explains, at the molecular level, how pMHC-specific information is transmitted across the T-cell membrane to initiate intracellular signaling. An in-depth understanding of this process will accelerate the rational design of immunotherapeutic agents targeting the TCR–CD3 complex.

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Section: Arguments For and Against Tcr Allosterymentioning

confidence: 99%

The structural basis of T-cell receptor (TCR) activation: An enduring enigma

2019

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“…Although allosteric propagation of biological signals over long distances has been demonstrated for many proteins, including cell-surface receptors such as the EphA2 receptor (52,53), the enormous diversity of TCRs poses a major conceptual challenge for allosteric models of T cell activation. How can conserved structural or dynamic changes in the TCR C␣ and C␤ domains, such as those in the C␣ AB loop and C␤ ␣A helix discussed above, be generated, given the diversity of TCR-pMHC binding interfaces and of V␣ and V␤ sequences?…”

Section: Allosteric Changes In T Cell Receptor Induced By Peptide-mhcmentioning

confidence: 99%

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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“…However, the exact roles of the Ig-like domain and the FnIII domain in defining the intermembrane distance are unclear. To address this issue, we evaluated the potential interactions of Sdks with lipid membranes using liposome pull-down assays, which had been used to examine the protein-lipid interactions (28,29). The liposomes were prepared with phosphatidylcholines, which is a major component of cell membrane, especially on the exoplasmic leaflet (29)(30)(31).…”

Section: Sdks Mediate Cell Adhesion Through the N-terminal Ig-like Domentioning

confidence: 99%

Architecture of cell–cell adhesion mediated by sidekicks

Tang

Chang

Dong

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Cell-cell adhesion is important for cell growth, tissue development, and neural network formation. Structures of cell adhesion molecules have been widely studied by crystallography, revealing the molecular details of adhesion interfaces. However, due to technical limitations, the overall structure and organization of adhesion molecules at cell adhesion interfaces has not been fully investigated. Here, we combine electron microscopy and other biophysical methods to characterize the structure of cell-cell adhesion mediated by the cell adhesion molecule Sidekick (Sidekick-1 and Sidekick-2) and obtain 3D views of the Sidekick-mediated adhesion interfaces as well as the organization of Sidekick molecules between cell membranes by electron tomography. The results suggest that the Ig-like domains and the fibronectin III (FnIII) domains of Sidekicks play different roles in cell adhesion. The Ig-like domains mediate the homophilic transinteractions bridging adjacent cells, while the FnIII domains interact with membranes, resulting in a tight adhesion interface between cells that may contribute to the specificity and plasticity of cell-cell contacts during cell growth and neural development.

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Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions

Cited by 34 publications

References 78 publications

The structural basis of T-cell receptor (TCR) activation: An enduring enigma

The structural basis of T-cell receptor (TCR) activation: An enduring enigma

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

Architecture of cell–cell adhesion mediated by sidekicks

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