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NUMBER  
AUTHOR Hwang, Wonmuk
TITLE Pre-T cell receptors topologically sample self-ligands during thymocyte beta-selection
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FILE  
JOURNAL SCIENCE, 2021
ABSTRACT Self-discrimination, a critical but ill-defined molecular process programmed during thymocyte development, requires myriad pre-T cell receptors (preTCRs) and alpha beta TCRs. Using x-ray crystallography, we show how a preTCR applies the concave beta-sheet surface of its single variable domain (V beta) to "horizontally" grab the protruding MHC alpha 2-helix. By contrast, alpha beta TCRs purpose all six complementarity-determining region (CDR) loops of their paired V alpha V beta module to recognize peptides bound to major histocompatibility complex molecules (pMHCs) in "vertical" head-to-head binding. The preTCR topological fit ensures that CDR3 beta reaches the peptide's featured C-terminal segment for pMHC sampling, establishing the subsequent alpha beta TCR canonical docking mode. "Horizontal" docking precludes germline CDR1 beta- and CDR2 beta-MHC binding to broaden beta-chain repertoire diversification before abTCR-mediated selection refinement. Thus, one subunit successively attunes the recognition logic of related multicomponent receptors.
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