Abstract
Germline mutations in the BRCA1 tumor suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. We report the X-ray crystal structure at a resolution of 1.85 Å of the BRCA1 tandem BRCT domains in complex with a phosphorylated peptide representing the minimal interacting region of the DEAH-box helicase BACH1. The structure reveals the determinants of this novel class of BRCA1 binding events. We show that a subset of disease-linked mutations act through specific disruption of phospho-dependent BRCA1 interactions rather than through gross structural perturbation of the tandem BRCT domains.
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Acknowledgements
We thank R. Scully and D. Livingston for vectors and helpful discussions, D. Livingston and R. Drapkin for the anti-BACH1 antibody, M. Glover for sharing unpublished information, members of the Yaffe and Smerdon laboratories for assistance and helpful comments, and S. Gamblin for assistance with crystal handling. This work was supported by US National Institutes of Health grant GM 60594 and a Burroughs-Wellcome Career Development Award to M.B.Y. D.L. was supported by a Howard Hughes Medical Institute predoctoral fellowship.
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Clapperton, J., Manke, I., Lowery, D. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol 11, 512–518 (2004). https://doi.org/10.1038/nsmb775
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DOI: https://doi.org/10.1038/nsmb775
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