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Structure of a BRCA1–BARD1 heterodimeric RING–RING complex

Nature Structural Biology volume 8, pages 833–837 (2001)Cite this article

Abstract

The RING domain of the breast and ovarian cancer tumor suppressor BRCA1 interacts with multiple cognate proteins, including the RING protein BARD1. Proper function of the BRCA1 RING domain is critical, as evidenced by the many cancer-predisposing mutations found within this domain. We present the solution structure of the heterodimer formed between the RING domains of BRCA1 and BARD1. Comparison with the RING homodimer of the V(D)J recombination-activating protein RAG1 reveals the structural diversity of complexes formed by interactions between different RING domains. The BRCA1–BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BRCA1 RING domain can be involved in associations with multiple protein partners and provides a framework for understanding cancer-causing mutations at the molecular level.

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Figure 1: Solution structure of the BRCA1–BARD1 heterodimer complex.
Figure 2: Structural comparison of RING–RING interactions.
Figure 3: Surface comparison and structural overlay of the BRCA1 and cCbl RING domains.
Figure 4: Stereo representation of the BRCA1–BARD1 RING domain heterodimer depicting the locations of mutations found within the BRCA1 (gray) and BARD1 (blue) RING domains8.

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Acknowledgements

We gratefully acknowledge J.E. Meza, E. Laughlin and D. Fox for technical assistance, and appreciate A. Weiner, J. McGourty, L. Spencer and P. Welcsh for careful reading of the manuscript. NMR experiments were performed, in part, in the Environmental Molecular Sciences Laboratory (a national scientific user facility sponsored by the DOE Biological and Environmental Research) located at the Pacific Northwest National Laboratory and operated for DOE by Battelle.

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Authors and Affiliations

  1. Department of Biochemistry and Biomolecular Structure Center, University of Washington, Seattle, 98195-7742, Washington, USA

    Peter S. Brzovic, Ponni Rajagopal & Rachel E. Klevit

  2. Environmental Molecular Science Laboratory, Pacific Northwest National Laboratories, Richland, 99352, Washington, USA

    David W. Hoyt

  3. Departments of Genetics and Medical Genetics, University of Washington, Seattle, 98195-7742, Washington, USA

    Mary-Claire King

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  1. Peter S. Brzovic
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  2. Ponni Rajagopal
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Correspondence to Rachel E. Klevit.

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Brzovic, P., Rajagopal, P., Hoyt, D. et al. Structure of a BRCA1–BARD1 heterodimeric RING–RING complex. Nat Struct Mol Biol 8, 833–837 (2001). https://doi.org/10.1038/nsb1001-833

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