Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection

Andrew C. McShan, Christine A. Devlin, Sarah A. Overall, Jihye Park, Jugmohit S. Toor, Danai Moschidi, David Flores-Solis, Hannah Choi, Sarvind Tripathi, Erik Procko, Nikolaos G. Sgourakis

Research output: Contribution to journalArticlepeer-review

Abstract

The 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 α2 domain of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α2 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 α12 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.

Original languageEnglish (US)
Pages (from-to)25602-25613
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number51
DOIs
StatePublished - Dec 17 2019

Keywords

  • Major histocompatibility complex
  • Molecular chaperone
  • NMR spectroscopy
  • Peptide editing
  • Peptide repertoire

ASJC Scopus subject areas

  • General

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