title: Diabetes-associated mutations in a beta-cell transcription factor destabilize an antiparallel "mini-zipper" in a dimerization interface.
abstract: Maturity-onset diabetes of the young, a monogenic form of Type II diabetes mellitus, is most commonly caused by mutations in hepatic nuclear factor 1alpha (HNF-1alpha). Here, the dimerization motif of HNF-1alpha is shown to form an intermolecular four-helix bundle. One face contains an antiparallel coiled coil whereas the other contains splayed alpha-helices. The "mini-zipper" is complementary in structure and symmetry to the top surface of a transcriptional coactivator (dimerization cofactor of homeodomains). The bundle is destabilized by a subset of mutations associated with maturity-onset diabetes of the young. Impaired dimerization of a beta-cell transcription factor thus provides a molecular mechanism of metabolic deregulation in diabetes mellitus.
authors.affiliation: Department of Biochemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4935, USA.
authors.forename: Q X
authors.initials: QX
authors.lastname: Hua
authors.forename: M
authors.initials: M
authors.lastname: Zhao
authors.forename: N
authors.initials: N
authors.lastname: Narayana
authors.forename: S H
authors.initials: SH
authors.lastname: Nakagawa
authors.forename: W
authors.initials: W
authors.lastname: Jia
authors.forename: M A
authors.initials: MA
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; 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; D006863:Hydrogen-Ion Concentration; D007515:Islets of Langerhans / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins; D017433:Protein Structure, Secondary; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
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