A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

Mahima Swamy, Katharina Beck-Garcia, Esmeralda Beck-Garcia, Frederike A. Hartl, Anna Morath, O. Sascha Yousefi, Elaine Pashupati Dopfer, Eszter Molnár, Anna K. Schulze, Raquel Blanco, Aldo Borroto, Nadia Martín-Blanco, Balbino Alarcon, Thomas Höfer, Susana Minguet, Wolfgang W A Schamel (Lead / Corresponding author)

Research output: Contribution to journalArticle

50 Citations (Scopus)
162 Downloads (Pure)

Abstract

Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.

Original languageEnglish
Pages (from-to)1091-1101
Number of pages11
JournalImmunity
Volume44
Issue number5
DOIs
Publication statusPublished - 17 May 2016

Fingerprint

T-Cell Antigen Receptor
Cholesterol
Phosphorylation
Allosteric Regulation
Adaptive Immunity
Signal Transduction
Phosphotransferases
Cell Membrane
Ligands
Lipids
Antigens

Cite this

Swamy, M., Beck-Garcia, K., Beck-Garcia, E., Hartl, F. A., Morath, A., Yousefi, O. S., ... Schamel, W. W. A. (2016). A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity, 44(5), 1091-1101. https://doi.org/10.1016/j.immuni.2016.04.011
Swamy, Mahima ; Beck-Garcia, Katharina ; Beck-Garcia, Esmeralda ; Hartl, Frederike A. ; Morath, Anna ; Yousefi, O. Sascha ; Dopfer, Elaine Pashupati ; Molnár, Eszter ; Schulze, Anna K. ; Blanco, Raquel ; Borroto, Aldo ; Martín-Blanco, Nadia ; Alarcon, Balbino ; Höfer, Thomas ; Minguet, Susana ; Schamel, Wolfgang W A. / A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. In: Immunity. 2016 ; Vol. 44, No. 5. pp. 1091-1101.
@article{77d665f45a964ebe8c20a710803e5c6c,
title = "A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation",
abstract = "Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.",
author = "Mahima Swamy and Katharina Beck-Garcia and Esmeralda Beck-Garcia and Hartl, {Frederike A.} and Anna Morath and Yousefi, {O. Sascha} and Dopfer, {Elaine Pashupati} and Eszter Moln{\'a}r and Schulze, {Anna K.} and Raquel Blanco and Aldo Borroto and Nadia Mart{\'i}n-Blanco and Balbino Alarcon and Thomas H{\"o}fer and Susana Minguet and Schamel, {Wolfgang W A}",
year = "2016",
month = "5",
day = "17",
doi = "10.1016/j.immuni.2016.04.011",
language = "English",
volume = "44",
pages = "1091--1101",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "5",

}

Swamy, M, Beck-Garcia, K, Beck-Garcia, E, Hartl, FA, Morath, A, Yousefi, OS, Dopfer, EP, Molnár, E, Schulze, AK, Blanco, R, Borroto, A, Martín-Blanco, N, Alarcon, B, Höfer, T, Minguet, S & Schamel, WWA 2016, 'A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation', Immunity, vol. 44, no. 5, pp. 1091-1101. https://doi.org/10.1016/j.immuni.2016.04.011

A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. / Swamy, Mahima; Beck-Garcia, Katharina; Beck-Garcia, Esmeralda; Hartl, Frederike A.; Morath, Anna; Yousefi, O. Sascha; Dopfer, Elaine Pashupati; Molnár, Eszter; Schulze, Anna K.; Blanco, Raquel; Borroto, Aldo; Martín-Blanco, Nadia; Alarcon, Balbino; Höfer, Thomas; Minguet, Susana; Schamel, Wolfgang W A (Lead / Corresponding author).

In: Immunity, Vol. 44, No. 5, 17.05.2016, p. 1091-1101.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation

AU - Swamy, Mahima

AU - Beck-Garcia, Katharina

AU - Beck-Garcia, Esmeralda

AU - Hartl, Frederike A.

AU - Morath, Anna

AU - Yousefi, O. Sascha

AU - Dopfer, Elaine Pashupati

AU - Molnár, Eszter

AU - Schulze, Anna K.

AU - Blanco, Raquel

AU - Borroto, Aldo

AU - Martín-Blanco, Nadia

AU - Alarcon, Balbino

AU - Höfer, Thomas

AU - Minguet, Susana

AU - Schamel, Wolfgang W A

PY - 2016/5/17

Y1 - 2016/5/17

N2 - Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.

AB - Signaling through the T cell receptor (TCR) controls adaptive immune responses. Antigen binding to TCRαβ transmits signals through the plasma membrane to induce phosphorylation of the CD3 cytoplasmic tails by incompletely understood mechanisms. Here we show that cholesterol bound to the TCRβ transmembrane region keeps the TCR in a resting, inactive conformation that cannot be phosphorylated by active kinases. Only TCRs that spontaneously detached from cholesterol could switch to the active conformation (termed primed TCRs) and then be phosphorylated. Indeed, by modulating cholesterol binding genetically or enzymatically, we could switch the TCR between the resting and primed states. The active conformation was stabilized by binding to peptide-MHC, which thus controlled TCR signaling. These data are explained by a model of reciprocal allosteric regulation of TCR phosphorylation by cholesterol and ligand binding. Our results provide both a molecular mechanism and a conceptual framework for how lipid-receptor interactions regulate signal transduction. The TCR can adopt an inactive, resting or an active, primed state. Schamel and colleagues show that the TCR is in equilibrium between these states. Peptide-MHC binding stabilizes the primed state that can be phosphorylated. Cholesterol binding stabilizes the resting state and thereby tunes the TCR activation threshold.

UR - http://www.scopus.com/inward/record.url?scp=84967142343&partnerID=8YFLogxK

U2 - 10.1016/j.immuni.2016.04.011

DO - 10.1016/j.immuni.2016.04.011

M3 - Article

C2 - 27192576

AN - SCOPUS:84967142343

VL - 44

SP - 1091

EP - 1101

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 5

ER -

Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS et al. A Cholesterol-Based Allostery Model of T Cell Receptor Phosphorylation. Immunity. 2016 May 17;44(5):1091-1101. https://doi.org/10.1016/j.immuni.2016.04.011