Mutational analysis of critical residues determining antigen presentation and activation of HLA-DQ0602 restricted T-cell clones

Reichstetter, Sandra; Papadopoulos, George K.; Moustakas, Antonis K.; Swanson, Eric S.; Liu, Andrew W.; Beheray, Sucheta; Ettinger, Ruth A.; Nepom, Gerald T.; Kwok, William W.

doi:10.1016/s0198-8859(01)00377-9

Cited by 21 publications

(26 citation statements)

References 36 publications

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“…Our results demonstrate a role for the polymorphisms at ␤9, ␤30, ␤57, ␤86, and ␤87 in controlling the peptide binding preferences in pockets 1, 6, and 9. These data further our understanding of DQ0602 and DQ0604, in conjunction with our previous studies identifying ␤57 as a key determinant in ␣␤ heterodimer stability and ␤70 in TCR recognition (21,22).…”

supporting

confidence: 85%

“…The explanation that we can provide for the contrasting roles of the DQ0602 and DQ0604 allelic proteins in the pathogenesis of T1D are a consequence of the differences in antigenic peptide motifs, ␣␤ heterodimer stability (21,51), and TCR recognition (22). The dominant protection associated with DQA1*0102-DQ␤1*0602 may originate from the unusual ␣␤ heterodimer stability of DQ0602 (51).…”

Section: Discussionmentioning

confidence: 83%

“…Models of DQ0602 and DQ0604 with the insulin B 5-15 peptide and its variants were prepared on a Silicon Graphics Indigo 2 work station using the program Insight II, version 2000 (Accelrys), essentially as previously described (22,27). The crystal structure of DQ0602 complexed to the hypocretin 1-13 peptide was used as a base molecule for all of the simulation studies (18).…”

Section: Molecular Modelingmentioning

confidence: 99%

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Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Ettinger

Papadopoulos

Moustakas

et al. 2006

The Journal of Immunology

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HLA-DQA1*0102-DQB1*0602 is associated with protection against type 1 diabetes (T1D). A similar allele, HLA-DQA1*0102-DQB1*0604, contributes to T1D susceptibility in certain populations but differs only at seven amino acids from HLA-DQA1*0102-DQB1*0602. Five of these polymorphisms are found within the peptide-binding groove, suggesting that differences in peptide binding contribute to the mechanism of their association with T1D. In this study, we determine the peptide-binding motif for HLA-DQA1*0102-DQB1*0604 allelic protein (DQ0604) in comparison to the established HLA-DQA1*0102-DQB1*0602 (DQ0602) motif using binding assays with model peptides from T1D autoantigens and homology modeling using the coordinates of the DQ0602-hypocretin 1–13 crystal structure. The peptide binding preferences were deduced with a peptide from insulin that bound both with a 2- to 3-fold difference in avidity using the same amino acids in the peptide as anchors. Peptide binding differences directly influenced by the polymorphisms in or nearby pockets 1, 6, and 9 were observed. In pocket 1, DQ0604 was better able to accommodate aromatic residues due to the β86 and β87 polymorphisms. A negatively charged amino acid was preferred by DQ0604 in pocket 6 due to the positively charged β30His. In pocket 9, DQ0604 preferred aromatic amino acids due to the β9 and β30 polymorphisms and had low tolerance of acidic residues. β57Val in DQ0604 functions differently than β57Ala, in that it pushes α76Arg outside of the pocket, preventing the formation of a salt bridge with an acidic amino acid in the peptide. This study furthers our understanding of the structure-function relationships of MHC class II polymorphisms.

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supporting

confidence: 85%

Section: Discussionmentioning

confidence: 83%

Section: Molecular Modelingmentioning

confidence: 99%

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Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Ettinger

Papadopoulos

Moustakas

et al. 2006

The Journal of Immunology

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“…24,35 The recently determined crystal structures of DQ2cis (DQA1*0501-DQB1*0201) 29 and DQ8cis (DQA1*0301-DQB1*0302) 25 were used as base molecules. The program Quanta (Accelrys, San Diego, CA, USA) was used to obtain a complete structure by providing the missing amino-acid residues from the crystal structure (for example, b105-112), as well as missing atoms from certain residues.…”

Section: Hla-dq-insulin Peptide Homology Modelingmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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“…Models of DR1401 with the Flu B HA 116-128 peptide and its variants were prepared on a Silicon Graphics Indigo 2 work station using the program Insight II, version 2000 (Accelrys, San Diego, CA, USA), essentially as previously described (12). Energy minimization at was performed at pH 5.4, the ambient pH for binding studies.…”

Section: Molecular Modelingmentioning

confidence: 99%

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

James

Moustakas

Berger

et al. 2008

Molecular Immunology

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This study identified the peptide-binding motif of HLA-DRB1*1401 (DR1401). First, peptides containing DR1401 restricted epitopes were identified using tetramer guided epitope mapping. Among these, an influenza B peptide was selected for the motif study. After confirming the binding register for this peptide using a set of arginine substitutions, binding affinities were determined for 33 peptides derived from this influenza B sequence with single amino acid substitutions. The DR1401 peptide binding motif was deduced from the relative binding affinities of these peptides and confirmed by structural modeling. Pocket 1 demonstrated a preference for aliphatic anchor residues and methionine. Pocket 4 accommodated methionine and aliphatic residues, but also allowed some polar and charged amino acids. Pocket 6 preferred basic residues but also allowed some polar and aliphatic amino acids. Pocket 9 preferred aliphatic and aromatic amino acids and tolerated some polar residues but excluded all charged residues. Together these preferences define a distinct set of peptides that can be presented by DR1401. The resulting motif was used to verify T cell epitopes within the novel antigenic peptides identified by tetramer guided epitope mapping and within peptides from published reports that contain putative DR1401 epitopes.

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Mutational analysis of critical residues determining antigen presentation and activation of HLA-DQ0602 restricted T-cell clones

Cited by 21 publications

References 36 publications

Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Allelic Variation in Key Peptide-Binding Pockets Discriminates between Closely Related Diabetes-Protective and Diabetes-SusceptibleHLA-DQB1*06Alleles

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Definition of the peptide binding motif within DRB1*1401 restricted epitopes by peptide competition and structural modeling

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