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.
Highlights
Increased risk of breast and ovarian cancers
Domain Boundary Determination—The C-terminal half of BARD1 encompasses a highly conserved region predicted to fold into three ANK repeats followed by tandem BRCT domains
A linker of approximately 40 residues with no homology to known domains is found between the ANK repeats and the BRCT domains and might include an additional ANK repeat
Summary
Increased risk of breast and ovarian cancers. Second, BARD1 is the constitutive nuclear partner of BRCA1. The sequence connecting the ARD and BRCT domains is important for BARD1 interactions with p53 and CstF-50 and contains two BARD1 breast and ovarian cancer-predisposing mutations, C557S and Q564H. Crystal Structure of the BARD1 Ankyrin Repeat Domain and the mechanism of interactions of the protein.
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