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
conformation and
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residues together, and an
between the two states. This mutation causes hydrogen bonds lost.
conformation and
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residues together, and an
between the two states. This mutation causes hydrogen bonds lost.
conformation and
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residues together, and an
between the two states. This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; interaction lost with BRCA1 interacting protein C-terminal helicase 1.
conformation and
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residues together, and an
between the two states. This mutation causes overpacking, and forms new hydrogen bonds.
conformation and
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residues together, and an
between the two states. This mutation causes overpacking, and forms new hydrogen bond.
conformation and
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residues together, and an
between the two states. This mutation causes hydrogen bonds lost, overpacking.
conformation and
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residues together, and an
between the two states. 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]. . .
