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

Marek Wieczorek, Jana Sticht, Sebastian Stolzenberg, Sebastian Günther, Christoph Wehmeyer, Zeina El Habre, Miguel Álvaro-Benito, Frank Noé () and Christian Freund ()
Additional contact information
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms13224 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13224

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms13224

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().