Structural Basis of Peptide Binding and Presentation by the Type I Diabetes-Associated MHC Class II Molecule of NOD Mice

Latek, Robert; Suri, Anish; Petzold, Shirley J.; Nelson, Christopher A.; Kanagawa, Osami; Unanue, Emil R.; Fremont, Daved H.

doi:10.1016/s1074-7613(00)80220-4

Cited by 177 publications

(191 citation statements)

References 46 publications

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“…The absence of this salt bridge in the case of diabetogenic class II MHC molecules generated a P9 pocket that was wider, shallower and open towards the Cterminus [9][10][11]. However, the effect of these unique structural features on peptide selection remained unclear: earlier reports that analyzed binding interactions with synthetic peptides or peptide libraries suggested that diabetogenic MHC molecules bound peptides promiscuously with little or no specificity [12][13][14][15].…”

Section: Biochemical Structural and Functional Properties Of Diabetementioning

confidence: 99%

“…Initial binding studies of the B:(9-23) peptide to soluble I-A g7 in detergent free conditions revealed poor binding and fast dissociation rates [10,13,14,40]. The IC 50 values for the B:(9-23) peptide were measured in the 5-10 μM range at endosomal pH and the half-life of the complexes was less than two hours.…”

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thmentioning

confidence: 99%

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Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

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One seminal aspect in autoimmune diabetes is antigen presentation of beta cell antigens by the diabetes-propensity class II histocompatibility molecules. The binding properties of I-A g7 molecules are reviewed here and an emphasis is placed on their selection of peptides with a highly specific sequence motif, in which one or more acidic amino acids are found at the carboxy end interacting at the P9 anchoring site of I-A g7 . The reasons for the central role of I-A g7 in the autoimmune response are analyzed. The insulin B chain segment 9-23 is a hot spot for T cell selection and a striking example of a weak MHC binding peptide that triggers autoreactivity.

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Section: Biochemical Structural and Functional Properties Of Diabetementioning

confidence: 99%

Section: Weak Mhc Binding Peptides and Autoreactivity: The Case Of Thmentioning

confidence: 99%

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Suri

Levisetti

Unanue

2008

Current Opinion in Immunology

Self Cite

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“…These residues are known to be critical for the peptide-binding function of the class II molecule. [59][60][61][62][63] In particular, aspartic acid (Asp) at residue 57, which is in pocket 9 of the HLA-DQB1 molecule, is encoded by a HLA-DQB protective allele, whilst an alanine, valine or serine residue at the same position characterises predisposing alleles. In the absence of aspartic acid the charge at the 'right hand' end of the peptide-binding pocket becomes more positive.…”

Section: Hla-encoded Susceptibility To T1dmentioning

confidence: 99%

Genetics of type 1 diabetes mellitus

2002

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“…Alternatively, or in addition to the loss of central tolerance, abnormalities of peripheral tolerance can be present, with some HLA alleles presenting specific peptides (such as islet cell peptides) to mature T lymphocytes that did not undergo negative selection. A number of investigators have advanced the hypothesis that HLA alleles associated with susceptibility to autoimmunity could be ªunstableº [54,55,56]. Though this hypothesis is feasible it is difficult to reconcile with the same HLA haplotypes associated with protection from diabetes and susceptibility for multiple sclerosis (e. g. DR2, DQB1*0602) or with the strong binding of insulin peptide B:9±23 to DQ8 whose crystal structure has recently been solved [57].…”

Section: Mechanisms Of Diabetogenicity Of Hla Moleculesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Structural Basis of Peptide Binding and Presentation by the Type I Diabetes-Associated MHC Class II Molecule of NOD Mice

Abstract: al., 1999). Nevertheless, a consensus I-A g7 binding motif has been difficult to establish from the sequence analysis and binding studies of naturally processed and synthetic peptides. One complication arises from the proposed weak interaction of I-A g7 with peptides (Reich et

Cited by 177 publications

References 46 publications

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Do the peptide-binding properties of diabetogenic class II molecules explain autoreactivity?

Genetics of type 1 diabetes mellitus

Genetic control of autoimmunity in Type I diabetes and associated disorders

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