Open AccessMolecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection
Author(s) -
Andrew C. McShan,
Christine A. Devlin,
Sarah A. Overall,
Jihye Park,
Jugmohit Toor,
Danai Moschidi,
David Flores-Solis,
Hannah Choi,
Sarvind Tripathi,
Erik Procko,
Nikolaos G. Sgourakis
Publication year - 2019
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1915562116
Subject(s) - major histocompatibility complex , biophysics , chaperone (clinical) , biology , epitope , mhc restriction , peptide , mhc class i , chemistry , microbiology and biotechnology , genetics , biochemistry , antigen , medicine , pathology
Significance The human population contains thousands of MHC-I alleles, showing a range of dependencies on molecular chaperones for loading of their peptide cargo, which are then displayed on the cell surface for T cell surveillance. Using the chaperone TAPBPR as a model, we combine deep mutagenesis with functional and biophysical data, especially solution NMR, to provide a complete view of the molecular determinants of chaperone recognition. Our data provide significant evidence that localized protein motions define the intrinsic ability of MHC-I molecules to interact with chaperones. The importance of MHC-I dynamics unifies our findings, with broad recognition of conformationally unstable, nascent MHC-I molecules becoming restricted to a smaller set of MHC-I alleles that retain relevant dynamic motions in their folded state.