The peptide binding motif of the disease associated HLA‐DQ (α 1* 0501, β 1* 0201) molecule

Vartdal, Frode; Johansen, B.V.; Friede, Thomas; Thorpe, Christopher J.; Stevanović, Stefan; Eriksen, Jon E.; Sletten, Knut; Thorsby, E.; Rammensee, Hans‐Georg; Sollid, Ludvig M.

doi:10.1002/eji.1830261132

Cited by 155 publications

(142 citation statements)

References 26 publications

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“…The IC 50 values for the analogues with N-methylation at P6 and P9 are virtually the same, whereas the off-rate is higher for the analogue with N-methylation at P6. A possible explanation for this is that the side chain of proline is a favorable anchor for the P6 pocket, but not for the P9 pocket (34,35), and that in gluten T-cell epitopes, the effect of the side chain interactions for proline will dominate over the lack of main chain interactions at the P6, but not the P9, position.…”

Section: Discussionmentioning

confidence: 99%

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Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Bergseng

Xia²,

Kim³

et al. 2005

Journal of Biological Chemistry

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Binding of peptide epitopes to major histocompatibility complex proteins involves multiple hydrogen bond interactions between the peptide main chain and major histocompatibility complex residues. The crystal structure of HLA-DQ2 complexed with the ␣I-gliadin epitope (LQPFPQPELPY) revealed four hydrogen bonds between DQ2 and peptide main chain amides. This is remarkable, given that four of the nine core residues in this peptide are proline residues that cannot engage in amide hydrogen bonding. Preserving main chain hydrogen bond interactions despite the presence of multiple proline residues in gluten peptides is a key element for the HLA-DQ2 association of celiac disease. We have investigated the relative contribution of each main chain hydrogen bond interaction by preparing a series of Nmethylated ␣I epitope analogues and measuring their binding affinity and off-rate constants to DQ2. Additionally, we measured the binding of ␣I-gliadin peptide analogues in which norvaline, which contains a backbone amide hydrogen bond donor, was substituted for each proline. Our results demonstrate that hydrogen bonds at P4 and P2 positions are most important for binding, whereas the hydrogen bonds at P9 and P6 make smaller contributions to the overall binding affinity. There is no evidence for a hydrogen bond between DQ2 and the P1 amide nitrogen in peptides without proline at this position. This is a unique feature of DQ2 and is likely a key parameter for preferential binding of proline-rich gluten peptides and development of celiac disease.

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Section: Discussionmentioning

confidence: 99%

“…In this respect it is interesting that invariant chain (i.e. CLIP) peptides are remarkably abundant among the endogenous peptides eluted from DQ2 molecules of B-cell lines (34,35).…”

Section: Discussionmentioning

confidence: 99%

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Bergseng

Xia²,

Kim³

et al. 2005

Journal of Biological Chemistry

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“…Recently, the crystal structures of DQ3.2 and IA g7 have been reported (15)(16)(17)(18)(19)(20). In terms of peptide-binding repertoires, peptide-binding assays and the sequencing of pools of eluted ligands have allowed definition of tentative motifs for DQ1, DQ2.3, DQ3.1, and DQ3.2 (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). These experiments have also yielded the sequences of several endogenously processed ligands for various DQ molecules.…”

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confidence: 99%

The HLA Molecules DQA10501/B10201 and DQA10301/B10302 Share an Extensive Overlap in Peptide Binding Specificity

Sidney

Guercio

Southwood

et al. 2002

The Journal of Immunology

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Assays to measure the binding capacity of peptides for HLA-DQA1*0501/B*0201 (DQ2.3) and DQA1*0301/B*0302 (DQ3.2) were developed using solubilized MHC molecules purified from EBV-transformed cell lines. These quantitative assays, based on the principle of the inhibition of binding of a high-affinity radiolabeled ligand, were validated by examining the binding capacity of known DQ-restricted epitopes or ligands. The availability of these assays allowed an investigation of patterns of cross-reactivity between different DQ molecules and with various common DR molecules. DQ2.3 and DQ3.2 were found to have significantly overlapping peptide binding repertoires. Specifically, of 13 peptides that bound either DQ2.3 or DQ3.2, nine (69.2%) bound both. The molecular basis of this high degree of cross-reactivity was further investigated with panels of single substitution analogs of the thyroid peroxidase 632–645Y epitope. It was found that DQ2.3 and DQ3.2 bind the same ligands by using similar anchor residues but different registers. These data suggest that in analogy to what was previously described for HLA-DR molecules, HLA-DQ supertypes characterized by largely overlapping binding repertoires can be defined. In light of the known linkage of both HLA-DQ2.3 and -DQ3.2 with insulin-dependent diabetes mellitus and celiac disease, these results might have important implications for understanding HLA class II autoimmune disease associations.

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“…The data also suggest the sequence AQFDHEAFL as the 9-mer core region with negative charges in positions P4 and P6 and a large hydrophobic residue in position P9 that are favorable for interaction with the sDQ2 peptide binding groove. This sequence contains alanine in position 1, which is not expected to be favorable due to its small size and the preference that HLA-DQ2 has for bulky hydrophobic anchor residues at this position (van de Wal et al 1996;Vartdal et al 1996). Notably, peptide binding to HLA-DQ2 is characterized by contributions from anchor residues in position 1, 4, 6, 7, and 9 (Kim et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Soluble HLA-DQ2 expressed in S2 cells copurifies with a high affinity insect cell derived protein

et al. 2008

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We here describe that soluble HLA-DQ2 (sDQ2) molecules, when expressed in Drosophila melanogaster S2 insect cells without a covalently tethered peptide, associate tightly with the D. melanogaster calcium binding protein DCB-45. The interaction between the proteins is stable in S2 cell culture and during affinity purification, which is done at high salt concentrations and pH 11.5. After affinity purification, the sDQ2/DCB-45 complex exists in substantial quantities next to a small amount of free heterodimeric sDQ2 and large amounts of aggregated sDQ2 free of DCB-45. Motivated by the stable complex formation and our interest in the development of reagents which inhibit HLA-DQ2 peptide binding, we have further characterized the sDQ2/DCB-45 interaction. Several lines of evidence indicate that an N-terminal fragment of DCB-45 is involved in the interaction with the peptide binding groove of sDQ2. Further mapping of this fragment of 54 residues identified a pentadecapeptide with high affinity for sDQ2 which may serve as a lead compound for the design of HLA-DQ2 blockers.

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The peptide binding motif of the disease associated HLA‐DQ (α 1* 0501, β 1* 0201) molecule

Cited by 155 publications

References 26 publications

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

The HLA Molecules DQA10501/B10201 and DQA10301/B10302 Share an Extensive Overlap in Peptide Binding Specificity

Soluble HLA-DQ2 expressed in S2 cells copurifies with a high affinity insect cell derived protein

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The peptide binding motif of the disease associated HLA‐DQ (α 1* 0501, β 1* 0201) molecule

Cited by 155 publications

References 26 publications

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

Main Chain Hydrogen Bond Interactions in the Binding of Proline-rich Gluten Peptides to the Celiac Disease-associated HLA-DQ2 Molecule

The HLA Molecules DQA1*0501/B1*0201 and DQA1*0301/B1*0302 Share an Extensive Overlap in Peptide Binding Specificity

Soluble HLA-DQ2 expressed in S2 cells copurifies with a high affinity insect cell derived protein

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The HLA Molecules DQA10501/B10201 and DQA10301/B10302 Share an Extensive Overlap in Peptide Binding Specificity