MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange
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Presentation of antigenic peptides by major histocompatibility complex class II (MHC-II) proteins determines T helper cell reactivity. The MHC-II genetic locus displays a large degree of allelic polymorphism influencing the peptide repertoire presented by the resulting MHC-II protein allotypes. During antigen processing, the human leukocyte antigen (HLA) molecule HLA-DM (DM) encounters these distinct allotypes and catalyzes exchange of the placeholder peptide CLIP by exploiting dynamic features of MHC-II. Here, we investigate 12 highly abundant CLIP-bound HLA-DRB1 allotypes and correlate dynamics to catalysis by DM. Despite large differences in thermodynamic stability, peptide exchange rates fall into a target range that maintains DM responsiveness. A DM-susceptible conformation is conserved in MHC-II molecules, and allosteric coupling between polymorphic sites affects dynamic states that influence DM catalysis. As exemplified for rheumatoid arthritis, we postulate that intrinsic dynamic features of peptide–MHC-II complexes contribute to the association of individual MHC-II allotypes with autoimmune disease.
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Abualrous, E. T., Stolzenberg, S., Sticht, J., Wieczorek, M., Roske, Y., Günther, M., Dähn, S., Boesen, B. B., Calvo, M. M., Biese, C., Kuppler, F., Medina-García, Á., Álvaro-Benito, M., Höfer, T., Noé, F., & Freund, C. (2023). MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange. Nature Chemical Biology, 19(10), 1196–1204. https://doi.org/10.1038/s41589-023-01316-3