MHC class II complexes sample intermediate states along the peptide exchange pathway.
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.
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Marek
M
Wieczorek
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Jana
J
Sticht
Computational Molecular Biology group, Institute for Mathematics, Arnimallee 6, 14195 Berlin, Germany.
Sebastian
S
Stolzenberg
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.|Institute of Human Virology, University of Maryland School of Medicine, 725 West Lombard Street, Baltimore, Maryland 21201, USA.
Sebastian
S
Günther
Computational Molecular Biology group, Institute for Mathematics, Arnimallee 6, 14195 Berlin, Germany.
Christoph
http://orcid.org/0000-0002-9526-0328
C
Wehmeyer
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Zeina
Z
El Habre
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Miguel
M
Álvaro-Benito
Computational Molecular Biology group, Institute for Mathematics, Arnimallee 6, 14195 Berlin, Germany.
Frank
F
Noé
Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195 Berlin, Germany.
Christian
C
Freund
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D006681:HLA-D Antigens / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D006681:HLA-D Antigens; C084245:HLA-DM antigens; D000949:Histocompatibility Antigens Class II; D010455:Peptides