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

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost, overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation probably decreased hydrophobic interaction.

conformation and Click here to see the residues together, and an between the two states.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

Very severe pathogenic mutations

conformation and Click here to see the 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 Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bond.

conformation and Click here to see the residues together, and an between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.

conformation and Click here to see the residues together, and an between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase.

Benign mutations

conformation and Click here to see the residues together, and an between the two states. This mutation forms the new hydrogen bond.

conformation and Click here to see the residues together, and an between the two states.

conformation and Click here to see the residues together, and an between the two states. This mutation decreased hydrophobic interaction and forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation is very interesting. There is rare interaction between 2 GLU resudues in Wild type, it is exchanged by saltbridge in the mutant.

conformation and Click here to see the residues together, and an between the two states. In contrast to the pathogenic mutation G1706E, this mutation causes only slight overpacking.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bond lost.

conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bond lost.

conformation and Click here to see the residues together, and an between the two states. This mutation forms new hydrogen bonds.

conformation and Click here to see the residues together, and an between the two states.

conformation and Click here to see the residues together, and an between the two states.