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| Item Type: | Article |
|---|---|
| Title: | MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange |
| Creators: |
Abualrous, E.T.  ORCID: https://orcid.org/0000-0001-9582-9089, Stolzenberg, S., Sticht, J. ORCID: https://orcid.org/0000-0002-4307-4726, Wieczorek, M., Roske, Y. ORCID: https://orcid.org/0000-0001-6237-388X, Günther, M., Dähn, S., Boesen, B.B., Calvo, M.M. ORCID: https://orcid.org/0009-0008-9179-127X, Biese, C., Kuppler, F., Medina-García, Á., Álvaro-Benito, M. ORCID: https://orcid.org/0000-0002-6019-3567, Höfer, T. ORCID: https://orcid.org/0000-0003-3560-8780, Noé, F. ORCID: https://orcid.org/0000-0003-4169-9324 and Freund, C. ORCID: https://orcid.org/0000-0001-7416-8226
|
| 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 |
| ISSN: | 1552-4450 |
| Publisher: | Nature Publishing Group |
| Volume: | 19 |
| Number: | 10 |
| 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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