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

Autor: Abualrous ET; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.; Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany.; Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt., Stolzenberg S; Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany., Sticht J; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.; Core Facility BioSupraMol, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Wieczorek M; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Roske Y; Max-Delbrück-Center for Molecular Medicine, Berlin, Germany., Günther M; Theoretische Systembiologie (B086), Deutsches Krebsforschungszentrum, Heidelberg, Germany., Dähn S; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Boesen BB; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Calvo MM; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Biese C; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Kuppler F; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Medina-García Á; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Álvaro-Benito M; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany., Höfer T; Theoretische Systembiologie (B086), Deutsches Krebsforschungszentrum, Heidelberg, Germany., Noé F; Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany. frank.noe@fu-berlin.de.; Microsoft Research AI4Science, Berlin, Germany. frank.noe@fu-berlin.de.; Department of Physics, Freie Universität Berlin, Berlin, Germany. frank.noe@fu-berlin.de.; Department of Chemistry, Rice University, Houston, TX, USA. frank.noe@fu-berlin.de., Freund C; Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany. christian.freund@fu-berlin.de.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2023 Oct; Vol. 19 (10), pp. 1196-1204. Date of Electronic Publication: 2023 May 04.
DOI: 10.1038/s41589-023-01316-3
Abstrakt: 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.
(© 2023. The Author(s).)
Databáze: MEDLINE
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