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.
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany; Division of Cell Signalling and Immunology, College of Life Sciences, University of Dundee, DD1 5EH, United Kingdom.
authors.forename: Mahima
authors.initials: M
authors.lastname: Swamy
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Beck-Garcia
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany; International Max Planck-Research School for Molecular and Cellular Biology, 79108 Freiburg, Germany.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Beck-Garcia
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Frederike A
authors.initials: FA
authors.lastname: Hartl
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Morath
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany.
authors.forename: O Sascha
authors.initials: OS
authors.lastname: Yousefi
authors.affiliation: Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Elaine Pashupati
authors.initials: EP
authors.lastname: Dopfer
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Eszter
authors.initials: E
authors.lastname: Molnár
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, 69120 Heidelberg, Germany; BioQuant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Schulze
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Aldo
authors.initials: A
authors.lastname: Borroto
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Martín-Blanco
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas - Universidad Autónoma de Madrid, 28049 Madrid, Spain.
authors.forename: Balbino
authors.initials: B
authors.lastname: Alarcon
authors.affiliation: Division of Theoretical Systems Biology, German Cancer Research Center, 69120 Heidelberg, Germany; BioQuant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
authors.affiliation: Department of Immunology, BIOSS Centre for Biological Signalling Studies, Faculty of Biology, and Centre for Chronic Immunodeficiency CCI, University Clinics Freiburg and Medical Faculty, Albert-Ludwigs-University of Freiburg, 79104 Freiburg, Germany; Max Planck-Institute of Immunbiology and Epigenetics, 79108 Freiburg, Germany. Electronic address: wolfgang.schamel@biologie.uni-freiburg.de.
authors.forename: Wolfgang W A
authors.initials: WW
authors.lastname: Schamel
mesh_terms: D056704:Adaptive Immunity; D000494:Allosteric Regulation; D000941:Antigens / Q000276:immunology / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D006649:Histocompatibility Antigens / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D018448:Models, Immunological; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000941:Antigens; D006649:Histocompatibility Antigens; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D002784:Cholesterol