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

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Item Type:Article
Title:MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange
Creators Name:Abualrous, E.T. and Stolzenberg, S. and Sticht, J. and Wieczorek, M. and Roske, Y. and Günther, M. and Dähn, S. and Boesen, B.B. and Calvo, M.M. and Biese, C. and Kuppler, F. and Medina-García, Á. and Álvaro-Benito, M. and Höfer, T. and Noé, F. and Freund, C.
Abstract: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.
Keywords:Enzyme Mechanisms, Immunology, NMR Spectroscopy, Peptides
Source:Nature Chemical Biology
Publisher:Nature Publishing Group
Page Range:1196-1204
Date:October 2023
Official Publication:https://doi.org/10.1038/s41589-023-01316-3
PubMed:View item in PubMed

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