Mutations in Brca1 BRCT Domains

Germline mutations in the BRCA1 tumor suppressor gene often result in a significant increase in susceptibility to breast and ovarian cancers. Although the molecular basis of their effects remains largely obscure, many mutations are known to target the highly conserved C-terminal BRCT repeats that function as a phosphoserine/phosphothreonine-binding module. We report the X-ray crystal structure at a resolution of 1.85 A of the BRCA1 tandem BRCT domains in complex with a phosphorylated peptide representing the minimal interacting region of the DEAH-box helicase BACH1. The structure reveals the determinants of this novel class of BRCA1 binding events. We show that a subset of disease-linked mutations act through specific disruption of phospho-dependent BRCA1 interactions rather than through gross structural perturbation of the tandem BRCT domains.^[1]

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. Pathogenic mutations are shown in magenta, benign mutations are shown in green, residues with both pathogenic and benign mutations are shown in plum.

Pathogenic mutations

To begin with scenes, please click in the following order: on "Wild type", after that "Mutation" and so on.

• Mutation T1685A: and the . . . This mutation causes hydrogen bonds lost.
• Mutation T1685I: and the . . . This mutation causes hydrogen bonds lost.
• Mutation R1699W: and the . . . This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; interaction lost with BRCA1 interacting protein C-terminal helicase 1.
• Mutation G1706E: and the . . . This mutation causes overpacking, and forms new hydrogen bonds.
• Mutation A1708E: and the . . . This mutation causes overpacking, and forms new hydrogen bond.
• Mutation S1715R: and the . . . This mutation causes hydrogen bonds lost, overpacking.
• Mutation G1738R: and the . . . This mutation causes overpacking.
• Mutation L1764P: and the . . . This mutation causes overpacking.
• Mutation L1764P: and the . This mutation probably decreased hydrophobic interaction.
• Mutation M1775R: (1t15) and (1n5o)^[2]. . .