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Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1

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Abstract

The C-terminal BRCT region of BRCA1 is essential for its DNA repair, transcriptional regulation and tumor suppressor functions. Here we determine the crystal structure of the BRCT domain of human BRCA1 at 2.5 Å resolution. The domain contains two BRCT repeats that adopt similar structures and are packed together in a head-to-tail arrangement. Cancer-causing missense mutations occur at the interface between the two repeats and destabilize the structure. The manner by which the two BRCT repeats interact in BRCA1 may represent a general mode of interaction between homologous domains within proteins that interact to regulate the cellular response to DNA damage. The structure provides a basis to predict the structural consequences of uncharacterized BRCA1 mutations.

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Figure 1: The two BRCT repeats form a single protein domain.
Figure 2: The structure of the dual repeat BRCT domain of BRCA1.
Figure 3: The packing of BRCT repeats.
Figure 4: Analysis of the structural consequences of mutations in the BRCT domain.

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Acknowledgements

We would like to thank L. Gaudreau for the gift of the BRCA1(1,568–1,863) expression plasmid and helpful discussions, B. Mark and J. Lamoureux for help with X-ray data collection, and K. Brister and the staff of APS BioCARS for excellent technical support during synchrotron data collection. This work was supported by operating grants from the Canadian Institutes of Health Research, the Canadian Breast Cancer Research Initiative and the Alberta Heritage Foundation for Medical Research.

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  1. Department of Biochemistry, University of Alberta, Edmonton, T6G 2H7, Alberta, Canada

    R. Scott Williams, Ruth Green & J.N. Mark Glover

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  1. R. Scott Williams
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  2. Ruth Green
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  3. J.N. Mark Glover
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Correspondence to J.N. Mark Glover.

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Williams, R., Green, R. & Glover, J. Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1. Nat Struct Mol Biol 8, 838–842 (2001). https://doi.org/10.1038/nsb1001-838

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