Abualrous, Esam T.Stolzenberg, SebastianSticht, JanaWieczorek, MarekRoske, YvetteGünther, MatthiasDähn, SteffenBoesen, Benedikt B.Calvo, Marcos MartínezBiese, CharlotteKuppler, FrankMedina-García, ÁlvaroÁlvaro-Benito, MiguelHöfer, ThomasNoé, FrankFreund, Christian2024-05-032024-05-032023Abualrous, 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/s41589-023-01316-3https://hdl.handle.net/1911/115620Presentation 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.engExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.Journal articles41589-023-01316-3https://doi.org/10.1038/s41589-023-01316-3