title: Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1.
abstract: The BRCT repeats in BRCA1 are essential for its tumor suppressor activity and interact with phosphorylated protein targets containing the sequence pSer-X-X-Phe, where X indicates any residue. The structure of the tandem BRCA1 BRCT repeats bound to an optimized phosphopeptide reveals that the N-terminal repeat harbors a conserved BRCT phosphoserine-binding pocket, while the interface between the repeats forms a hydrophobic groove that recognizes the phenylalanine. Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition. The diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Williams
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lee
authors.forename: D Duong
authors.initials: DD
authors.lastname: Hau
authors.forename: J N Mark
authors.initials: JN
authors.lastname: Glover
mesh_terms: D000595:Amino Acid Sequence; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D005260:Female; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D010748:Phosphopeptides / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014162:Transfection
chemical_list: D019313:BRCA1 Protein; D010748:Phosphopeptides