title: Diabetes mutations delineate an atypical POU domain in HNF-1alpha.
abstract: Mutations in Hnf-1alpha are the most common Mendelian cause of diabetes mellitus. To elucidate the molecular function of a mutational hotspot, we cocrystallized human HNF-1alpha 83-279 with a high-affinity promoter and solved the structure of the complex. Two identical protein molecules are bound to the promoter. Each contains a homeodomain and a second domain structurally similar to POU-specific domains that was not predicted on the basis of amino acid sequence. Atypical elements in both domains create a stable interface that further distinguishes HNF-1alpha from other flexible POU-homeodomain proteins. The numerous diabetes-causing mutations in HNF-1alpha thus identified a previously unrecognized POU domain which was used as a search model to identify additional POU domain proteins in sequence databases.
authors.affiliation: Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.forename: J Daniel
authors.initials: JD
authors.lastname: Frantz
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Oh
authors.forename: Lone
authors.initials: L
authors.lastname: Hansen
authors.forename: Sirano
authors.initials: S
authors.lastname: Dhe-Paganon
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D003062:Codon; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins; D050809:POU Domain Factors; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D014158:Transcription, Genetic; D014961:X-Ray Diffraction
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D050809:POU Domain Factors; D011994:Recombinant Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA