title: Quantitative Analysis of the Association Angle between T-cell Receptor Vα/Vβ Domains Reveals Important Features for Epitope Recognition.
abstract: T-cell receptors (TCR) play an important role in the adaptive immune system as they recognize pathogen- or cancer-based epitopes and thus initiate the cell-mediated immune response. Therefore there exists a growing interest in the optimization of TCRs for medical purposes like adoptive T-cell therapy. However, the molecular mechanisms behind T-cell signaling are still predominantly unknown. For small sets of TCRs it was observed that the angle between their Vα- and Vβ-domains, which bind the epitope, can vary and might be important for epitope recognition. Here we present a comprehensive, quantitative study of the variation in the Vα/Vβ interdomain-angle and its influence on epitope recognition, performing a systematic bioinformatics analysis based on a representative set of experimental TCR structures. For this purpose we developed a new, cuboid-based superpositioning method, which allows a unique, quantitative analysis of the Vα/Vβ-angles. Angle-based clustering led to six significantly different clusters. Analysis of these clusters revealed the unexpected result that the angle is predominantly influenced by the TCR-clonotype, whereas the bound epitope has only a minor influence. Furthermore we could identify a previously unknown center of rotation (CoR), which is shared by all TCRs. All TCR geometries can be obtained by rotation around this center, rendering it a new, common TCR feature with the potential of improving the accuracy of TCR structure prediction considerably. The importance of Vα/Vβ rotation for signaling was confirmed as we observed larger variances in the Vα/Vβ-angles in unbound TCRs compared to epitope-bound TCRs. Our results strongly support a two-step mechanism for TCR-epitope: First, preformation of a flexible TCR geometry in the unbound state and second, locking of the Vα/Vβ-angle in a TCR-type specific geometry upon epitope-MHC association, the latter being driven by rotation around the unique center of rotation.
authors.affiliation: Department of Biosciences and Center for Integrated Protein Science Munich,Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hoffmann
authors.affiliation: Medizinische Klinik III, Innere Medizin mit Schwerpunkt Hämatologie und Onkologie, Technische Universität München, Munich, Germany; Clinical Cooperation Group, Antigen specific T cell therapy, Helmholtz Zentrum München (GmbH), German Center for Environmental Health, Munich, Germany; German Cancer Consortium (DKTK), Munich, Germany.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Krackhardt
authors.affiliation: Department of Biosciences and Center for Integrated Protein Science Munich,Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Antes
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018604:Epitope Mapping / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry* / Q000276:immunology / Q000648:ultrastructure*; D008956:Models, Chemical; D018448:Models, Immunological; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure*
chemical_list: D018984:Epitopes, T-Lymphocyte; D016693:Receptors, Antigen, T-Cell, alpha-beta