Pre-T cell receptors topologically sample self-ligands during thymocyte -selection. uri icon

abstract

  • Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and TCRs. Using x-ray crystallography, we show how a preTCR applies the concave -sheet surface of its single variable domain (V) to "horizontally" grab the protruding MHC 2-helix. By contrast, TCRs purpose all six complementarity-determining region (CDR) loops of their paired VV module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in "vertical" head-to-head binding. The preTCR topological fit ensures that CDR3 reaches the peptide's featured C-terminal segment for pMHC sampling, establishing the subsequent TCR canonical docking mode. "Horizontal" docking precludes germline CDR1- and CDR2-MHC binding to broaden -chain repertoire diversification before TCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.

published proceedings

  • Science

author list (cited authors)

  • Li, X., Mizsei, R., Tan, K., Mallis, R. J., Duke-Cohan, J. S., Akitsu, A., ... Reinherz, E. L.

complete list of authors

  • Li, Xiaolong||Mizsei, Réka||Tan, Kemin||Mallis, Robert J||Duke-Cohan, Jonathan S||Akitsu, Aoi||Tetteh, Paul W||Dubey, Abhinav||Hwang, Wonmuk||Wagner, Gerhard||Lang, Matthew J||Arthanari, Haribabu||Wang, Jia-Huai||Reinherz, Ellis L