HLA‐B27: a registry of constitutive peptide ligands

Castro, José A. Łópez de; Álvarez, Iñaki; Marcilla, Miguel; Paradela, Alberto; Ramos, Manuel; Sesma, Laura; Vázquez, Manuel

doi:10.1111/j.0001-2815.2004.00220.x

Cited by 91 publications

(161 citation statements)

References 52 publications

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“…Since peptide-elution studies have shown the HLA-B*2705 B-pocket binds almost exclusively arginine [12,28], variable viruses may thus readily escape immune recognition by any alteration of P2. Interestingly two subtly different mechanisms of binding the P2R have been observed in different crystal structures.…”

Section: Discussionmentioning

confidence: 99%

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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We have solved the crystal structures of three HLA‐B*2705–peptide complexes with the immunodominant viral peptides: EBV EBNA3C 258–266 (RRIYDLIEL), influenza (flu) nucleoprotein NP383–391 (SRYWAIRTR), and HIV gag 264–273 (KRWIILGLNK). Long‐term non‐progression during HIV infection has been associated with presentation by HLA‐B*2705, and T cell recognition, of the highly immunodominant KRWIILGLNK peptide. The tight hydrogen‐bonding network observed between the HLA‐B*2705 B‐pocket and the peptide P2 arginine guanadinium anchor explains why mutation of this residue during HIV infection results in loss of peptide binding, immune escape and progression to AIDS. Prominent, solvent‐exposed structures within these peptides may participate in generating T cell responses to these immunodominant epitopes. In the HLA‐B*2705 complex with flu NP383–391, the amino acid side chains of residues 4, 7 and 8 are solvent‐exposed whilst in the HIV decamer, the main‐chain bulges into the solvent around P7. Thus, HLA‐B*2705 presents viral peptides in a range of conformations. Tetrameric complexes of HLA‐B*2705 with the HIV and flu but not EBV peptides bound strongly to the killer‐Ig‐like receptor (KIR)3DL1. Substitution of EBV P8 glutamate to threonine allowed recognition by KIR3DL1. In the HLA‐B*2705–EBV structure the P8 glutamate side chain is solvent‐exposed and may inhibit KIR3DL1 binding through electrostatic forces.See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425875

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Section: Discussionmentioning

confidence: 99%

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

et al. 2005

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“…We first looked for evidence of extended versions of peptides identified in either ERAP1-silenced cells or ERAP1-competent cells. As shown in Table 1 (28,(32)(33)(34).…”

Section: Erap1 In Hla-b27 Peptide Presentation 287mentioning

confidence: 99%

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

Chen

Fischer

Peng

et al. 2014

Arthritis & Rheumatology

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Objective. HLA-B27 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are the two strongest genetic factors predisposing to ankylosing spondylitis (AS). A key aminopeptidase in class I major histocompatibility complex presentation, ERAP1 potentially contributes to the pathogenesis of AS by altering HLA-B27 peptide presentation. The aim of this study was to analyze the effects of ERAP1 on the HLA-B27 peptide repertoire and peptide presentation to cytotoxic T lymphocytes (CTLs).Methods. ERAP1-silenced and -competent HeLa.B27 and C1R.B27 cells were isotope-labeled, mixed, lysed, and then immunoprecipitated using W6/32 or ME1 antibodies. Peptides bound to HLA-B27 were eluted and analyzed by tandem mass spectrometry. Selected peptides were synthesized and tested for HLA-B27 binding ability. The effect of ERAP1 silencing/ mutation on presentation of an immunodominant viral HLA-B27 epitope, KK10, to CTLs was also studied.Results. In both HeLa.B27 and C1R.B27 cells, the proportion of 9-mer HLA-B27-bound peptides was decreased by ERAP1 silencing, whereas the percentages of longer peptides (11-13 mer) were increased. Surprisingly, following ERAP1 silencing, C-terminally extended peptides were readily identified. These were better able to bind to HLA-B27 than were N-terminally extended peptides lacking an arginine at position 2. In both HeLa.B27 cells and mouse fibroblasts expressing HLA-B27, the absence of ERAP1 reduced peptide recognition by HLA-B27-restricted KK10-specific CTLs following infection with recombinant vaccinia virus or transfection with minigenes expressing KK10 precursors. Presence of an AS-protective variant of ERAP1, K528R, as compared to wild-type ERAP1, reduced the peptide recognition by KK10 CTLs following transfection with extended KK10 minigenes.Conclusion. These results show that ERAP1 directly alters peptide binding and presentation by HLA-B27, thus demonstrating a potential pathogenic mechanism in AS. Inhibition of ERAP1 could potentially be used for treatment of AS and other ERAP1-associated diseases.The human leukocyte antigen HLA-B27 is very strongly associated with development of the common inflammatory rheumatic disease ankylosing spondylitis (AS). However, the pathogenic mechanism remains unclear. Recent genome-wide association studies have identified additional AS-associated genes, of which the strongest association is with endoplasmic reticulum aminopeptidase 1 (ERAP1) (1). The strong genetic association of AS with ERAP1 single-nucleotide polymorphisms has been confirmed in different populations (2-7).

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“…A statistical analysis was then performed as previously described. 40 Briefly, the frequency of each amino acid residue in a given peptide position was normalized against the mean frequency of that residue among the human proteins (http://www.ebi.ac.uk/integr8/StatsAminoPage.do?org ProteomeId ¼ 25), using the w 2 -test with Yates' correction. Bonferroni correction (P-value Â 20) was then applied.…”

Section: Matrix Generationmentioning

confidence: 99%

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

et al. 2011

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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.

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HLA‐B27: a registry of constitutive peptide ligands

Cited by 91 publications

References 52 publications

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Crystal structures and KIR3DL1 recognition of three immunodominant viral peptides complexed to HLA‐B*2705

Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA–B27

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

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