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interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance. Here, we demonstrate that the molecular chaperone TAP-binding protein related (TAPBPR) associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized toward the \u03b1<sub>2</sub> domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the \u03b1<sub>2</sub> domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at \"hotspot\" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the \u03b1<sub>1</sub>/\u03b1<sub>2</sub> helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of 1) chaperoning unstable MHC-I molecules with broad allele-specificity at early stages of their folding process, and 2) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, toward editing the repertoire of displayed antigens.","bibjson":{"author":[{"initials":"AC","lastname":"McShan","name":"McShan AC"},{"initials":"CA","lastname":"Devlin","name":"Devlin CA"},{"initials":"SA","lastname":"Overall","name":"Overall SA"},{"initials":"J","lastname":"Park","name":"Park J"},{"initials":"JS","lastname":"Toor","name":"Toor JS"},{"initials":"D","lastname":"Moschidi","name":"Moschidi D"},{"initials":"D","lastname":"Flores-Solis","name":"Flores-Solis D"},{"initials":"H","lastname":"Choi","name":"Choi H"},{"initials":"S","lastname":"Tripathi","name":"Tripathi S"},{"initials":"E","lastname":"Procko","name":"Procko E"},{"initials":"NG","lastname":"Sgourakis","name":"Sgourakis NG"}],"identifier":[{"id":"10.1073/pnas.1915562116","type":"doi"},{"id":"31796585","type":"pubmed"}],"issue":["51"],"journal":{"iso_abbreviation":"Proc. 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