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

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.

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., 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. 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
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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