title: The Allostery Model of TCR Regulation.
abstract: The activity of the αβ TCR is controlled by conformational switches. In the resting conformation, the TCR is not phosphorylated and is inactive. Binding of multivalent peptide-MHC to the TCR stabilizes the active conformation, leading to TCR signaling. These two conformations allow the TCRs to be allosterically regulated. We review recent data on heterotropic allostery where peptide-MHC and membrane cholesterol serve opposing functions as positive and negative allosteric regulators, respectively. In resting T cells cholesterol keeps TCRs in the resting conformation that otherwise would become spontaneously active. This regulation is well described by the classical Monod-Wyman-Changeux model of allostery. Moreover, the observation that TCRs assemble into nanoclusters might allow for homotropic allostery, in which individual TCRs could positively cooperate and thus enhance the sensitivity of T cell activation. This new view of TCR regulation will contribute to a better understanding of TCR functioning.
authors.affiliation: Department of Immunology, Institute for Biology III, Faculty of Biology, University of Freiburg, 79108 Freiburg, Germany; wolfgang.schamel@biologie.uni-freiburg.de.|BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.|Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
authors.forename: Wolfgang W A
authors.initials: WW
authors.lastname: Schamel
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; and.|BioQuant Center, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Höfer
authors.affiliation: Department of Immunology, Institute for Biology III, Faculty of Biology, University of Freiburg, 79108 Freiburg, Germany.|BIOSS Centre for Biological Signaling Studies, University of Freiburg, 79104 Freiburg, Germany.
authors.forename: Susana
authors.initials: S
authors.lastname: Minguet
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D008958:Models, Molecular; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology
chemical_list: D011948:Receptors, Antigen, T-Cell