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Pre–T cell receptors topologically sample self-ligands during thymocyte b-selection


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. , Reinherz E.L. . Science. 2020 ; 371(6525). 181-185


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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.