Pre-T cell receptors topologically sample self-ligands during thymocyte {beta}-selection

Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre–T cell receptors (preTCRs) and αβTCRs. Using x-ray crystallography, we show how a preTCR applies the concave β-sheet surface of its single variable domain (Vβ) to "horizontally" grab the protruding MHC α2-helix. By contrast, αβTCRs purpose all six complementarity-determining region (CDR) loops of their paired VαVβ module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in "vertical" head-to-head binding. The preTCR topological fit ensures that CDR3β reaches the peptide’s featured C-terminal segment for pMHC sampling, establishing the subsequent αβTCR canonical docking mode. "Horizontal" docking precludes germline CDR1β- and CDR2β-MHC binding to broaden β-chain repertoire diversification before αβTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.

Source: ScienceNOW - January 7, 2021 Category: Science Authors: Li, X., Mizsei, R., Tan, K., Mallis, R. J., Duke-Cohan, J. S., Akitsu, A., Tetteh, P. W., Dubey, A., Hwang, W., Wagner, G., Lang, M. J., Arthanari, H., Wang, J.-h., Reinherz, E. L. Tags: Biochemistry, Immunology reports Source Type: news