Rxivist logo

Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 73,401 bioRxiv papers from 319,519 authors.

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

By 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

Posted 24 Sep 2019
bioRxiv DOI: 10.1101/779777 (published DOI: 10.1073/pnas.1915562116)

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 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 towards one side of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the alpha2 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 alpha1/2 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 i) chaperoning unstable MHC-I molecules at early stages of their folding process, akin to a holdase with broad allele-specificity, and ii) 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, towards editing the repertoire of displayed antigens.

Download data

  • Downloaded 249 times
  • Download rankings, all-time:
    • Site-wide: 47,584 out of 73,413
    • In immunology: 1,094 out of 1,909
  • Year to date:
    • Site-wide: 43,736 out of 73,413
  • Since beginning of last month:
    • Site-wide: 43,736 out of 73,413

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News