PMID- 37142807 OWN - NLM STAT- MEDLINE DCOM- 20230928 LR - 20231003 IS - 1552-4469 (Electronic) IS - 1552-4450 (Print) IS - 1552-4450 (Linking) VI - 19 IP - 10 DP - 2023 Oct TI - MHC-II dynamics are maintained in HLA-DR allotypes to ensure catalyzed peptide exchange. PG - 1196-1204 LID - 10.1038/s41589-023-01316-3 [doi] AB - 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. CI - (c) 2023. The Author(s). FAU - Abualrous, Esam T AU - Abualrous ET AUID- ORCID: 0000-0001-9582-9089 AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. AD - Department of Mathematics and Computer Science, Freie Universitat Berlin, Berlin, Germany. AD - Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt. FAU - Stolzenberg, Sebastian AU - Stolzenberg S AD - Department of Mathematics and Computer Science, Freie Universitat Berlin, Berlin, Germany. FAU - Sticht, Jana AU - Sticht J AUID- ORCID: 0000-0002-4307-4726 AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. AD - Core Facility BioSupraMol, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Wieczorek, Marek AU - Wieczorek M AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Roske, Yvette AU - Roske Y AD - Max-Delbruck-Center for Molecular Medicine, Berlin, Germany. FAU - Gunther, Matthias AU - Gunther M AD - Theoretische Systembiologie (B086), Deutsches Krebsforschungszentrum, Heidelberg, Germany. FAU - Dahn, Steffen AU - Dahn S AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Boesen, Benedikt B AU - Boesen BB AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Calvo, Marcos Martinez AU - Calvo MM AUID- ORCID: 0009-0008-9179-127X AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Biese, Charlotte AU - Biese C AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Kuppler, Frank AU - Kuppler F AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Medina-Garcia, Alvaro AU - Medina-Garcia A AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Alvaro-Benito, Miguel AU - Alvaro-Benito M AUID- ORCID: 0000-0002-6019-3567 AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. FAU - Hofer, Thomas AU - Hofer T AUID- ORCID: 0000-0003-3560-8780 AD - Theoretische Systembiologie (B086), Deutsches Krebsforschungszentrum, Heidelberg, Germany. FAU - Noe, Frank AU - Noe F AUID- ORCID: 0000-0003-4169-9324 AD - Department of Mathematics and Computer Science, Freie Universitat Berlin, Berlin, Germany. frank.noe@fu-berlin.de. AD - Microsoft Research AI4Science, Berlin, Germany. frank.noe@fu-berlin.de. AD - Department of Physics, Freie Universitat Berlin, Berlin, Germany. frank.noe@fu-berlin.de. AD - Department of Chemistry, Rice University, Houston, TX, USA. frank.noe@fu-berlin.de. FAU - Freund, Christian AU - Freund C AUID- ORCID: 0000-0001-7416-8226 AD - Protein Biochemistry, Institute for Chemistry and Biochemistry, Freie Universitat Berlin, Berlin, Germany. christian.freund@fu-berlin.de. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230504 PL - United States TA - Nat Chem Biol JT - Nature chemical biology JID - 101231976 RN - 0 (HLA-D Antigens) RN - 0 (HLA-DR Antigens) RN - 0 (Peptides) SB - IM MH - Humans MH - *HLA-D Antigens/metabolism MH - *HLA-DR Antigens/metabolism MH - Peptides/chemistry MH - Antigen Presentation MH - Catalysis MH - Protein Binding PMC - PMC10522485 COIS- The authors declare no competing interests. EDAT- 2023/05/05 00:42 MHDA- 2023/09/28 06:42 PMCR- 2023/05/04 CRDT- 2023/05/04 23:29 PHST- 2022/09/10 00:00 [received] PHST- 2023/03/17 00:00 [accepted] PHST- 2023/09/28 06:42 [medline] PHST- 2023/05/05 00:42 [pubmed] PHST- 2023/05/04 23:29 [entrez] PHST- 2023/05/04 00:00 [pmc-release] AID - 10.1038/s41589-023-01316-3 [pii] AID - 1316 [pii] AID - 10.1038/s41589-023-01316-3 [doi] PST - ppublish SO - Nat Chem Biol. 2023 Oct;19(10):1196-1204. doi: 10.1038/s41589-023-01316-3. Epub 2023 May 4.