RING fingers, which are found in a number of different proteins, are cysteine-rich sequences that coordinate the binding of two zinc ions and appear to promote the ubiquitination of proteins, among other functions. The RING finger in BRCA1 specifically interacts with another similar RING finger protein known as BARD1, which was recently identified based on this interaction. Rachel Klevit and colleagues at the University of Washington report the solution structure of the RING domain of BRCA1 in complex with the RING domain of BARD1. The illustration to the left shows a ribbon diagram of the two RING subunits: the BRCA1 subunit (green) contains three α-helices and three β-strands, while the BARD1 subunit (purple) contains two α-helices and two β-strands. Two α-helices from each subunit pair in an antiparallel fashion to form a stable four-helix bundle, placing the sequences that bind zinc ions (shown as circles) in direct apposition to one another. The authors point out that several mutations that cause breast or ovarian cancer map to the zinc-binding regions or the BRCA1 –BARD1 dimerization surface.
Both BARD1 and BRCA1 also share another conserved sequence known as the BRCT domain, a phylogenetically conserved sequence found in proteins involved in DNA repair and cell-cycle regulation. In the second report, Mark Glover and colleagues at the University of Alberta, Canada, determine the crystal structure of the C-terminal BRCT region of BRCA1 at 2.5Å resolution. The illustration to the right shows the structure of the two BRCT repeats (one in blue and the other in yellow), which have adopted similar structures and are packed together in a head to tail arrangement. The structure provides the first evidence that these repeats assemble into a stable unit that is resistant to limited proteolysis. Two of the best-characterized BRCA1 cancer-causing mutations occur at the interface between the two repeats and the authors show that these mutations reduce the proteolytic stability of the composite structure.
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