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A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes.

A L Corper·T Stratmann·V Apostolopoulos·C A Scott·K C Garcia·A S Kang·I A Wilson·L Teyton
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Abstract

Susceptibility to murine and human insulin-dependent diabetes mellitus correlates strongly with major histocompatibility complex (MHC) class II I-A or HLA-DQ alleles that lack an aspartic acid at position beta57. I-Ag7 lacks this aspartate and is the only class II allele expressed by the nonobese diabetic mouse. The crystal structure of I-Ag7 was determined at 2.6 angstrom resolution as a complex with a high-affinity peptide from the autoantigen glutamic acid decarboxylase (GAD) 65. I-Ag7 has a substantially wider peptide-binding groove around beta57, which accounts for distinct peptide preferences compared with other MHC class II alleles. Loss of Asp(beta57) leads to an oxyanion hole in I-Ag7 that can be filled by peptide carboxyl residues or, perhaps, through interaction with the T cell receptor.

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AllelesAmino Acid MotifsAmino Acid SequenceAnimalsAspartic AcidCrystallography, X-RayDiabetes Mellitus, Type 1Drosophila melanogasterGenes, MHC Class IIGlutamate DecarboxylaseHistocompatibility Antigens Class IIHumansHydrogen BondingMiceMice, Inbred NODModels, MolecularMolecular Sequence DataPeptide LibraryProtein BindingProtein ConformationProtein Structure, SecondaryReceptors, Antigen, T-CellRecombinant ProteinsJournal ArticleResearch Support, Non-U.S. Gov'tResearch Support, U.S. Gov't, P.H.S.

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A L Corper, T Stratmann, V Apostolopoulos, C A Scott, K C Garcia, A S Kang, I A Wilson, L Teyton. 2000-04-21. A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes.. https://doi.org/10.1126/science.288.5465.505

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