Structure of a BRCA1-BARD1 heterodimeric RING-RING complex

The RING domain of the breast and ovarian cancer tumor suppressor BRCA1 int eracts with multiple cognate proteins, including the RING protein BARD1. Pr oper function of the BRCA1 RING domain is critical, as evidenced by the man y cancer-predisposing mutations found within this domain. We present the so lution structure of the heterodimer formed between the RING domains of BRCA 1 and BARD1. Comparison with the RING homodimer of the V(D)J recombination- activating protein RAG1 reveals the structural diversity of complexes forme d by Interactions between different RING domains. The BRCA1-BARD1 structure provides a model for its ubiquitin ligase activity, illustrates how the BR CA1 RING domain can be involved in associations with multiple protein partn ers and provides a framework for understanding cancer-causing mutations at the molecular level.