title: The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles.
abstract: The objective of this study was to characterize the peptide-binding motif of the major histocompatibility complex (MHC) class II HLA-DR8 molecule included in the type 1 diabetes-associated haplotype DRB1(*)0801-DQA1(*)0401/DQB1(*)0402 (DR8-DQ4), and compare it with that of other diabetes-associated MHC class II alleles; DR8-bound peptides were eluted from an HLA-DR homozygous lymphoblastoid cell line. The repertoire was characterized by peptide sequencing using a LTQ ion trap mass spectrometer coupled to a multidimensional liquid chromatography system. After validation of the spectra identification, the definition of the HLA-DR8 peptide-binding motif was achieved from the analysis of 486 natural ligands, based on serial alignments of all possible HLA-DR-binding cores. The DR8 motif showed a strong similarity with the peptide-binding motifs of other MHC class II diabetes-associated alleles, HLA-DQ8 and H-2 I-A(g7). Similar to HLA-DQ8 and H-2 I-A(g7), HLA-DR8 preferentially binds peptides with an acidic residue at position P9 of the binding core, indicating that DR8 is the susceptibility component of the DR8-DQ4 haplotype. Indeed, some DR8 peptides were identical to peptides previously identified as DQ8- or I-A(g7) ligands, and several diabetes-specific peptides associated with DQ8 or I-A(g7) could theoretically bind to HLA-DR8. These data further strengthen the association of HLA-DR8 with type I diabetes.
authors.affiliation: Department of Cell Biology, Physiology and Immunology, Immunology Unit, Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Muixí
authors.forename: M
authors.initials: M
authors.lastname: Gay
authors.forename: P M
authors.initials: PM
authors.lastname: Muñoz-Torres
authors.forename: C
authors.initials: C
authors.lastname: Guitart
authors.forename: J
authors.initials: J
authors.lastname: Cedano
authors.forename: J
authors.initials: J
authors.lastname: Abian
authors.forename: I
authors.initials: I
authors.lastname: Alvarez
authors.forename: D
authors.initials: D
authors.lastname: Jaraquemada
mesh_terms: D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002461:Cell Line, Transformed; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D059810:HLA-DR Serological Subtypes / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D059810:HLA-DR Serological Subtypes; C041559:HLA-DR8 antigen; D010455:Peptides