title: Structural basis of dimerization, coactivator recognition and MODY3 mutations in HNF-1alpha.
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.
authors.affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, California 94720-3206, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Rose
authors.forename: J H
authors.initials: JH
authors.lastname: Bayle
authors.forename: J A
authors.initials: JA
authors.lastname: Endrizzi
authors.forename: J D
authors.initials: JD
authors.lastname: Cronk
authors.forename: G R
authors.initials: GR
authors.lastname: Crabtree
authors.forename: T
authors.initials: T
authors.lastname: Alber
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D019281:Dimerization; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006860:Hydrogen Bonding; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins; D017433:Protein Structure, Secondary; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D006836:Hydro-Lyases; C076392:pterin-4a-carbinolamine dehydratase