Mutations in BRCA1/BARD1 RING-domain heterodimer

spinqualitylabelsall models Human BRCA1 ring domain complex with BARD1 ring domain and Zn+2 ions (PDB code 1jm7) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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. Pathogenic and benign mutations in RING domain. Pathogenic mutations are shown in magenta, benign mutations are shown in green. Pathogenic mutations Pathogenic mutations in RING domain. Mutation L22S: conformation and Click here to see the residues together, and an between the two states. Putative new hydrogen bonds were added. Mutation T37K: conformation and Click here to see the residues together, and an between the two states. Mutation C39R: conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond. Mutation H41R: conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of N-Zn bond. Mutation C44S: conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond. Mutation C44Y: conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond. Very severe pathogenic mutation Mutation C61G: conformation and Click here to see the residues together, and an between the two states. This mutation causes missing of S-Zn bond. Benign mutations Mutation K45Q: conformation and Click here to see the residues together, and an between the two states. Mutation D67Y: conformation and Click here to see the residues together, and an between the two states.

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Alexander Berchansky, Jaime Prilusky, Michal Harel, Joel L. Sussman