Quantitative Analysis of the Association Angle between T-cell Receptor Vα/Vβ Domains Reveals Important Features for Epitope Recognition

PLoS Comput Biol. 2015 Jul 17;11(7):e1004244. doi: 10.1371/journal.pcbi.1004244. eCollection 2015 Jul.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Epitope Mapping / methods
  • Epitopes, T-Lymphocyte / chemistry*
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / ultrastructure*
  • Models, Chemical*
  • Models, Immunological
  • Models, Molecular*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Receptors, Antigen, T-Cell, alpha-beta / chemistry
  • Receptors, Antigen, T-Cell, alpha-beta / immunology*
  • Receptors, Antigen, T-Cell, alpha-beta / ultrastructure*

Substances

  • Epitopes, T-Lymphocyte
  • Receptors, Antigen, T-Cell, alpha-beta

Grants and funding

TH and IA were funded by: CIPSM cluster of excellence; http://www.dfg.de/ SFB1035; http://www.dfg.de/. AMK was funded by: DJCLS R11/23; https://www.carreras-stiftung.de/ F2-F5121.7.3-10c/23932; http://www.bayimmunet.de/ 110281; http://www.krebshilfe.de. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.