The peptide-binding motif of HLA-DR8 shares important structural features with other type 1 diabetes-associated alleles

L. Muixí, M. Gay, P. M. Mũoz-Torres, C. Guitart, J. Cedano, J. Abian, I. Alvarez, D. Jaraquemada

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13 Citations (Scopus)

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. © 2011 Macmillan Publishers Limited All rights reserved.
Original languageEnglish
Pages (from-to)504-512
JournalGenes and Immunity
Volume12
DOIs
Publication statusPublished - 20 Oct 2011

Keywords

  • MHC alleles
  • peptide-binding motifs
  • peptides
  • type 1 diabetes

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