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MHC class II complexes sample intermediate states along the peptide exchange pathway

Author

Listed:
  • Marek Wieczorek

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Jana Sticht

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Sebastian Stolzenberg

    (Computational Molecular Biology group, Institute for Mathematics)

  • Sebastian Günther

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin
    Institute of Human Virology, University of Maryland School of Medicine)

  • Christoph Wehmeyer

    (Computational Molecular Biology group, Institute for Mathematics)

  • Zeina El Habre

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Miguel Álvaro-Benito

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin)

  • Frank Noé

    (Computational Molecular Biology group, Institute for Mathematics)

  • Christian Freund

    (Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin)

Abstract

The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII’s ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual’s MHC restricted immune response.

Suggested Citation

  • Marek Wieczorek & Jana Sticht & Sebastian Stolzenberg & Sebastian Günther & Christoph Wehmeyer & Zeina El Habre & Miguel Álvaro-Benito & Frank Noé & Christian Freund, 2016. "MHC class II complexes sample intermediate states along the peptide exchange pathway," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13224
    DOI: 10.1038/ncomms13224
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