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Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer

Nature Structural & Molecular Biology volume 11, pages 512–518 (2004)Cite this article

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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Figure 1: Structure of the tandem BRCT domain–BACH1 phosphopeptide complex.
Figure 2: BRCT cancer-linked mutations and sequence conservation in relation to the BACH1 phosphopeptide-binding site.
Figure 3: Functional effects of tandem BRCT domain mutations.
Figure 4: The Phe(+3) position of the BACH1 phosphopeptide is essential for tandem BRCT domain binding specificity.
Figure 5: Localization of the BRCT domains to nuclear phosphoproteins.

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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for vectors and helpful discussions, D. Livingston and R. Drapkin for the anti-BACH1 antibody, M. Glover for sharing unpublished information, members of the Yaffe and Smerdon laboratories for assistance and helpful comments, and S. Gamblin for assistance with crystal handling.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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  1. Julie A Clapperton and Isaac A Manke: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Protein Structure, National Institute for Medical Research, The Ridgeway, Mill Hill, London, NW7 1AA, UK

    Julie A Clapperton, Lesley F Haire & Stephen J Smerdon

  2. Center for Cancer Research, E18-580, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, 02139, Massachusetts, USA

    Isaac A Manke, Drew M Lowery, Timmy Ho & Michael B Yaffe

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  1. Julie A Clapperton
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Correspondence to Michael B Yaffe or Stephen J Smerdon.

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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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