Cholesterol and Sphingomyelin Drive Ligand-independent T-cell Antigen Receptor Nanoclustering

Molnár, Éva D.; Swamy, Mahima; Holzer, Martin; Beck-García, Katharina; Worch, Remigiusz; Thiele, Christoph; Guigas, Gernot; Boye, Kristian; Luescher, Immanuel F.; Schwille, Petra; Schubert, Rolf; Schamel, Wolfgang W. A.

doi:10.1074/jbc.m112.386045

Cited by 144 publications

(134 citation statements)

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“…The function of this acidic TM residue is unknown (discussed in ref. 16), but its location identifies the "exposed" TCRβ helix face as a region of interest in potential oligomeric TCR interactions (43)(44)(45) and associations with particular lipid or sterol moieties that have been shown to regulate receptor activation (46,47). Several groups have proposed models of TCR-CD3 arrangements based on extracellular domain interactions.…”

Section: Discussionmentioning

confidence: 99%

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Krshnan

Park

et al. 2016

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

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The T-cell antigen receptor (TCR) is an assembly of eight type I single-pass membrane proteins that occupies a central position in adaptive immunity. Many TCR-triggering models invoke an alteration in receptor complex structure as the initiating event, but both the precise subunit organization and the pathway by which ligandinduced alterations are transferred to the cytoplasmic signaling domains are unknown. Here, we show that the receptor complex transmembrane (TM) domains form an intimately associated eighthelix bundle organized by a specific interhelical TCR TM interface. The salient features of this core structure are absolutely conserved between αβ and γδ TCR sequences and throughout vertebrate evolution, and mutations at key interface residues caused defects in the formation of stable TCRαβ:CD3δe:CD3γe:ζζ complexes. These findings demonstrate that the eight TCR-CD3 subunits form a compact and precisely organized structure within the membrane and provide a structural basis for further investigation of conformationally regulated models of transbilayer TCR signaling.T-cell receptor | transmembrane structure | NMR | MD simulation | cysteine cross-linking T he antigen-specific T-cell response depends critically upon the ability of the T-cell receptor (TCR) to signal the recognition of activating ligands. The variable TCR proteins (α, β, δ, and γ) that bind to these ligands have no intrinsic intracellular signaling capability and transmit information through the noncovalently associated CD3δe, CD3γe, and ζζ modules containing cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) that are phosphorylated by the Src-family kinase Lck. The mechanism by which antigen sensing is translated from ligand binding at the distal end of the TCR to phosphorylation events at the cytoplasmic tails of the associated signaling modules remains an important open question in T-cell biology. A mounting pool of evidence implicates ligand-induced alterations in receptor structure (1) and/or TCR-CD3 configuration (2-6) as the triggering event. Changes in the structured extracellular (EC) domains are proposed to translate, through an unknown mechanism, into alterations in the CD3 and ζζ cytoplasmic tails, converting them to a conformation that is receptive to phosphorylation by Lck and binding of other proximal signaling components (7-12). This type of signaling model implies a pathway between EC and cytoplasmic domains that may involve alterations in the subunit transmembrane (TM) domains with respect to each other and/ or the lipid bilayer (13-16). Consistent with this view, Kuhns and colleagues (17) recently reported a ligand-induced change in intersubunit proximity at the TM-juxtamembrane juncture in the ζζ dimer and proposed that this "mechanical switch" is coupled to signal initiation at the ζζ cytoplasmic tails. However, the nature of the upstream structural changes that trigger this switch, and whether it is required for signal initiation, remain to be determined. Tracing possible transbilayer conformational pathway...

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Section: Discussionmentioning

confidence: 99%

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Krshnan

Park

et al. 2016

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

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“…Because the presence of cholesterol has also been found to be important for the oligomerization of various membrane proteins (39,40), we wondered whether cholesterol also has an effect on the distribution of oligomeric states of SERT. Upon depletion of plasma membrane cholesterol via cholesterol oxidase, however, the distribution of the complexes was not altered (Fig.…”

Section: C Obtained Brightness Distribution Of the Oligomeric Fractimentioning

confidence: 99%

Single Molecule Analysis Reveals Coexistence of Stable Serotonin Transporter Monomers and Oligomers in the Live Cell Plasma Membrane

Anderluh

Klotzsch

Reismann

et al. 2014

Journal of Biological Chemistry

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Background:The serotonin transporter (SERT) terminates synaptic signaling by reuptake of the neurotransmitter serotonin. Results: Interaction kinetics and number of subunits are elucidated by single molecule brightness analysis of SERT complexes. Conclusion:The oligomeric state of SERT complexes is stably determined before being integrated into the plasma membrane. Significance: The results reveal the first evidence for kinetic trapping of preformed neurotransmitter transporter oligomers.

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“…Although many factors could underlie the inter-individual variation of Vγ9Vδ2 T-cell activities, studies indicate that metabolic resources, namely lipids such as cholesterol, could affect Vγ9Vδ2 T-cell activation and functions (23)(24)(25)(26)(27). Cholesterol, an essential component of membranes, regulates membrane fluidity and thus affects various receptor-mediated signal transduction pathways.…”

Section: Introductionmentioning

confidence: 99%

Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

Rodrigues

Correia

Mensurado

et al. 2018

Cancer Immunology Research

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Cholesterol and Sphingomyelin Drive Ligand-independent T-cell Antigen Receptor Nanoclustering

Cited by 144 publications

References 51 publications

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

A conserved αβ transmembrane interface forms the core of a compact T-cell receptor–CD3 structure within the membrane

Single Molecule Analysis Reveals Coexistence of Stable Serotonin Transporter Monomers and Oligomers in the Live Cell Plasma Membrane

Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells

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