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

Journal Article · · Nature Chemical Biology
 [1];  [2];  [2];  [2];  [3];  [4];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [4];  [5];  [2]
  1. Freie Univ., Berlin (Germany); Ain Shams University, Cairo (Egypt)
  2. Freie Univ., Berlin (Germany)
  3. Max-Delbrück-Center for Molecular Medicine, Berlin (Germany)
  4. Deutsches Krebsforschungszentrum, Heidelberg (Germany)
  5. Freie Univ., Berlin (Germany); Microsoft Research AI4Science, Berlin (Germany); Rice Univ., Houston, TX (United States)
+ Show Author Affiliations
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.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
2469824
Journal Information:
Nature Chemical Biology, Journal Name: Nature Chemical Biology Journal Issue: 10 Vol. 19; ISSN 1552-4450
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
NMR spectroscopy
enzyme mechanisms
immunology
peptides