MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange

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dc.citation.firstpage1196en_US
dc.citation.issueNumber10en_US
dc.citation.journalTitleNature Chemical Biologyen_US
dc.citation.lastpage1204en_US
dc.citation.volumeNumber19en_US
dc.contributor.authorAbualrous, Esam T.en_US
dc.contributor.authorStolzenberg, Sebastianen_US
dc.contributor.authorSticht, Janaen_US
dc.contributor.authorWieczorek, Mareken_US
dc.contributor.authorRoske, Yvetteen_US
dc.contributor.authorGünther, Matthiasen_US
dc.contributor.authorDähn, Steffenen_US
dc.contributor.authorBoesen, Benedikt B.en_US
dc.contributor.authorCalvo, Marcos Martínezen_US
dc.contributor.authorBiese, Charlotteen_US
dc.contributor.authorKuppler, Franken_US
dc.contributor.authorMedina-García, Álvaroen_US
dc.contributor.authorÁlvaro-Benito, Miguelen_US
dc.contributor.authorHöfer, Thomasen_US
dc.contributor.authorNoé, Franken_US
dc.contributor.authorFreund, Christianen_US
dc.date.accessioned2024-05-03T15:51:19Zen_US
dc.date.available2024-05-03T15:51:19Zen_US
dc.date.issued2023en_US
dc.description.abstractPresentation 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.en_US
dc.identifier.citationAbualrous, 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/s41589-023-01316-3en_US
dc.identifier.digitals41589-023-01316-3en_US
dc.identifier.doihttps://doi.org/10.1038/s41589-023-01316-3en_US
dc.identifier.urihttps://hdl.handle.net/1911/115620en_US
dc.language.isoengen_US
dc.publisherSpringer Natureen_US
dc.rightsExcept 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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleMHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchangeen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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