title: Crystal structure of the BARD1 ankyrin repeat domain and its functional consequences.
abstract: BARD1 is the constitutive nuclear partner to the breast and ovarian cancer-specific tumor suppressor BRCA1. Together, they form a heterodimeric complex responsible for maintaining genomic stability through nuclear functions involving DNA damage signaling and repair, transcriptional regulation, and cell cycle control. We report the 2.0A structure of the BARD1 ankyrin repeat domain. The structure includes four ankyrin repeats with a non-canonical C-terminal capping ankyrin repeat and a well ordered extended loop preceding the first repeat. Conserved surface features show an acidic patch and an acidic pocket along the surface typically used by ankyrin repeat domains for binding cognate proteins. We also demonstrate that two reported mutations, N470S and V507M, in the ankyrin repeat domain do not result in observable structural defects. These results provide a structural basis for exploring the biological function of the ankyrin repeat domain and for modeling BARD1 isoforms.
authors.affiliation: Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fox
authors.forename: Isolde
authors.initials: I
authors.lastname: Le Trong
authors.forename: Ponni
authors.initials: P
authors.lastname: Rajagopal
authors.forename: Peter S
authors.initials: PS
authors.lastname: Brzovic
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Stenkamp
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Klevit
mesh_terms: D000595:Amino Acid Sequence; D017487:Ankyrins / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism*; D018360:Crystallography, X-Ray / Q000379:methods; D004926:Escherichia coli / Q000378:metabolism; D019143:Evolution, Molecular; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008954:Models, Biological; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D017487:Ankyrins; D025521:Tumor Suppressor Proteins; C102449:BARD1 protein, human; D044767:Ubiquitin-Protein Ligases