title: Unraveling the structural basis for the unusually rich association of human leukocyte antigen DQ2.5 with class-II-associated invariant chain peptides.
abstract: Human leukocyte antigen (HLA)-DQ2.5 (DQA1*05/DQB1*02) is a class-II major histocompatibility complex protein associated with both type 1 diabetes and celiac disease. One unusual feature of DQ2.5 is its high class-II-associated invariant chain peptide (CLIP) content. Moreover, HLA-DQ2.5 preferentially binds the non-canonical CLIP2 over the canonical CLIP1. To better understand the structural basis of HLA-DQ2.5's unusual CLIP association characteristics, better insight into the HLA-DQ2.5·CLIP complex structures is required. To this end, we determined the X-ray crystal structure of the HLA-DQ2.5· CLIP1 and HLA-DQ2.5·CLIP2 complexes at 2.73 and 2.20 Å, respectively. We found that HLA-DQ2.5 has an unusually large P4 pocket and a positively charged peptide-binding groove that together promote preferential binding of CLIP2 over CLIP1. An α9-α22-α24-α31-β86-β90 hydrogen bond network located at the bottom of the peptide-binding groove, spanning from the P1 to P4 pockets, renders the residues in this region relatively immobile. This hydrogen bond network, along with a deletion mutation at α53, may lead to HLA-DM insensitivity in HLA-DQ2.5. A molecular dynamics simulation experiment reported here and recent biochemical studies by others support this hypothesis. The diminished HLA-DM sensitivity is the likely reason for the CLIP-rich phenotype of HLA-DQ2.5.
authors.affiliation: the Bioinformatics Institute, Singapore 138671, Singapore.|the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Thanh-Binh
authors.initials: TB
authors.lastname: Nguyen
authors.affiliation: the Department of Biological Sciences, National University of Singapore, Singapore 117543, Singapore.
authors.forename: Priya
authors.initials: P
authors.lastname: Jayaraman
authors.affiliation: the Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, N-0372 Oslo, Norway.
authors.forename: Elin
authors.initials: E
authors.lastname: Bergseng
authors.affiliation: the Bioinformatics Institute, Singapore 138671, Singapore.|the Indian Institute of Science Education and Research, Pune 411008, India, and.
authors.forename: M S
authors.initials: MS
authors.lastname: Madhusudhan
authors.affiliation: From the Department of Chemistry and ckim7@utep.edu.|School of Pharmacy, University of Texas at El Paso, El Paso, Texas 79968.|Synthetic Biology for Clinical and Technological Innovation, Life Sciences Institute, National University of Singapore, 117456 Singapore, Singapore.
authors.forename: Chu-Young
authors.initials: CY
authors.lastname: Kim
authors.affiliation: the Centre for Immune Regulation and Department of Immunology, University of Oslo and Oslo University Hospital, N-0372 Oslo, Norway l.m.sollid@medisin.uio.no.
authors.forename: Ludvig M
authors.initials: LM
authors.lastname: Sollid
mesh_terms: D001665:Binding Sites; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics; D059848:HLA-DQ alpha-Chains / Q000737:chemistry* / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics
chemical_list: D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C053186:HLA-DQ2 antigen; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D010455:Peptides
keywords: HLA-DM; HLA-DQ; X-ray crystallography; autoimmune disease; celiac disease; major histocompatibility complex (MHC); molecular dynamics; type 1 diabetes