7YXB

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

Summary for 7YXB

• Entry DOI: 10.2210/pdb7yxb/pdb
• Descriptor: HLA class II histocompatibility antigen, DR alpha chain, HLA class II histocompatibility antigen DR beta chain, CLIP peptide, ... (6 entities in total)
• Functional Keywords: hla-dr4, clip peptide, mhcii, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 96446.13

Authors

Roske, Y.,Abualrous, E.T.,Freund, C. (deposition date: 2022-02-15, release date: 2023-02-22, Last modification date: 2024-02-07)

Primary citation

Abualrous, E.T.,Stolzenberg, S.,Sticht, J.,Wieczorek, M.,Roske, Y.,Gunther, M.,Dahn, S.,Boesen, B.B.,Calvo, M.M.,Biese, C.,Kuppler, F.,Medina-Garcia, A.,Alvaro-Benito, M.,Hofer, T.,Noe, F.,Freund, C.
MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange.
Nat.Chem.Biol., 19:1196-1204, 2023

PubMed 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.

PubMed: 37142807
DOI: 10.1038/s41589-023-01316-3

Experimental method

X-RAY DIFFRACTION (2.095 Å)