Abstract
Maturity-onset diabetes of the young type 3 (MODY3) results from mutations in the transcriptional activator hepatocyte nuclear factor-1alpha (HNF-1alpha). Several MODY3 mutations target the HNF-1alpha dimerization domain (HNF-p1), which binds the coactivator, dimerization cofactor of HNF-1 (DCoH). To define the mechanism of coactivator recognition and the basis for the MODY3 phenotype, we determined the cocrystal structure of the DCoH-HNF-p1 complex and characterized biochemically the effects of MODY3 mutations in HNF-p1. The DCoH-HNF-p1 complex comprises a dimer of dimers in which HNF-p1 forms a unique four-helix bundle. Through rearrangements of interfacial side chains, a single, bifunctional interface in the DCoH dimer mediates both HNF-1alpha binding and formation of a competing, transcriptionally inactive DCoH homotetramer. Consistent with the structure, MODY3 mutations in HNF-p1 reduce activator function by two distinct mechanisms.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Binding Sites
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Crystallography, X-Ray
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DNA-Binding Proteins*
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Diabetes Mellitus, Type 2 / genetics*
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Dimerization
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-alpha
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Hepatocyte Nuclear Factor 1-beta
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Humans
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Hydro-Lyases / antagonists & inhibitors
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Hydro-Lyases / chemistry
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Hydro-Lyases / metabolism*
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Hydrogen Bonding
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Models, Biological
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Models, Molecular
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Mutation / genetics*
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Nuclear Proteins*
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Protein Structure, Secondary
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Substrate Specificity
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Transcription Factors / chemistry*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcriptional Activation
Substances
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DNA-Binding Proteins
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HNF1A protein, human
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HNF1B protein, human
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Hepatocyte Nuclear Factor 1-alpha
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Nuclear Proteins
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Transcription Factors
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Hepatocyte Nuclear Factor 1
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Hepatocyte Nuclear Factor 1-beta
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Hydro-Lyases
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pterin-4a-carbinolamine dehydratase