title: Threading analysis of the Pitx2 homeodomain: predicted structural effects of mutations causing Rieger syndrome and iridogoniodysgenesis.
abstract: Mutations in the homeobox gene PITX2 are responsible for a range of clinical phenotypes involving ocular and craniofacial development. Several mutations within the Pitx2 homeodomain region are specifically responsible for the development of the related autosomal-dominant disorders Rieger syndrome and iridogoniodysgenesis. To address the question of the structural effect of disease-causing mutations on the Pitx2 homeodomain, we used threading techniques to examine the tertiary structure of the Pitx2 wild-type and mutant homeodomain, using the crystal structure of Drosophila engrailed homeodomain bound with DNA as a template [Kissinger et al., 1990]. The threading analysis reveals that the wild-type Pitx2 homeodomain is indeed capable of forming the typical three-helical bundle-fold characteristic of homeodomain proteins. Energy calculations indicate that the homeodomain structure is stabilized primarily by hydrophobic interactions between residues at the helical interface. Point mutations responsible for the development of these genetic disorders were also examined; the results suggest that these mutations lead to the inability of Pitx2 to adopt its proper structure and bind to the regulatory sequences of its target gene(s), which in turn affects its metabolic role in the cell. Published 1999 Wiley-Liss, Inc.
authors.affiliation: Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: S
authors.initials: S
authors.lastname: Banerjee-Basu
authors.forename: A D
authors.initials: AD
authors.lastname: Baxevanis
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002151:Calorimetry; D017124:Conserved Sequence; D019465:Craniofacial Abnormalities / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics; D005799:Genes, Dominant; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D007498:Iris / Q000002:abnormalities* / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D017354:Point Mutation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D013816:Thermodynamics; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C101485:homeobox protein PITX1; C433629:homeobox protein PITX3