MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange.
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
10
09
2022
accepted:
17
03
2023
medline:
28
9
2023
pubmed:
5
5
2023
entrez:
4
5
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37142807
doi: 10.1038/s41589-023-01316-3
pii: 10.1038/s41589-023-01316-3
pmc: PMC10522485
doi:
Substances chimiques
HLA-D Antigens
0
HLA-DR Antigens
0
Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1196-1204Informations de copyright
© 2023. The Author(s).
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