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Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

Nature Structural & Molecular Biology volume 11, pages 519–525 (2004)Cite this article

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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Figure 1: Overview of the BRCA1 BRCT–peptide complex.
Figure 2: Details of BRCA1 BRCT–peptide interactions.
Figure 3: Ability of mutant forms of the BRCA1 BRCT domain to bind pSer-containing peptides.
Figure 4: Structure determination of variant V1809F.
Figure 5: Occlusion of the Phe(+3)-binding pocket by BRCA1 missense mutations V1809F and M1775R.

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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 We thank M. Yaffe and S. Smerdon for sharing unpublished data and the gift of biotinylated peptide libraries, and R. Boyko for help with BRCT sequence alignments.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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  1. Department of Biochemistry, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    R Scott Williams, Megan S Lee, D Duong Hau & J N Mark Glover

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Correspondence to J N Mark Glover.

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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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