Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1.
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.
Williams
R Scott
RS
Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.
Lee
Megan S
MS
Hau
D Duong
DD
Glover
J N Mark
JN
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
D019313:BRCA1 Protein; D010748:Phosphopeptides