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.
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Acknowledgements
We are grateful to J. Parrish, E. Bergmann, T. Moraes, J. Holton and the Berkeley Centre for Structural Biology staff for discussions and technical support during data collection. Data was collected on Advanced Light Source beamline 8.3.1 with funding from the Alberta Synchrotron Institute as part of a participating research team. We thank M. Yaffe and S. Smerdon for sharing unpublished data and the gift of biotinylated peptide libraries, and R. Boyko for help with BRCT sequence alignments. This work was supported by a grant from the Canadian Breast Cancer Research Alliance. J.N.M.G. is a Canada research chair in structural molecular biology.
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Williams, R., Lee, M., Hau, D. et al. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nat Struct Mol Biol 11, 519–525 (2004). https://doi.org/10.1038/nsmb776
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DOI: https://doi.org/10.1038/nsmb776