Mutations in Brca1 BRCT Domains

spinqualitylabelsall models Human BRCA1 (blue) complex with phosphoserine-containing BRCA1 interacting protein C-terminal helicase 1 (olive) (PDB code 1t15) Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D 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. Brca1 BRCT domains in complex with the phosphorylated interacting region from Bach1 Helicase. Pathogenic and benign mutations in BRCT domain. 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 Mutation T1685A: conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost. Mutation T1685I: conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost. Mutation G1706E: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bonds. Mutation S1715R: conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bonds lost, overpacking. Mutation G1738R: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking. Mutation L1764P: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking. Mutation I1766S: conformation and Click here to see the residues together, and an between the two states. This mutation probably decreased hydrophobic interaction. Mutation C1787S: conformation and Click here to see the residues together, and an between the two states. Mutation G1788V: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking. Mutation V1838E: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking. Very severe pathogenic mutations Mutation R1699W: 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. Mutation A1708E: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking, and forms new hydrogen bond. Mutation M1775R: 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. Mutation M1775K: 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 Mutation M1652T: conformation and Click here to see the residues together, and an between the two states. This mutation forms the new hydrogen bond. Mutation M1652I: conformation and Click here to see the residues together, and an between the two states. Mutation F1662S: 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. Mutation L1664P: conformation and Click here to see the residues together, and an between the two states. This mutation causes overpacking. Mutation E1682K: 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. Mutation G1706A: 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. Mutation T1720A: conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bond lost. Mutation R1751Q: conformation and Click here to see the residues together, and an between the two states. This mutation causes hydrogen bond lost. Mutation V1804D: conformation and Click here to see the residues together, and an between the two states. This mutation forms new hydrogen bonds. Mutation I1858L: conformation and Click here to see the residues together, and an between the two states. Mutation P1859R: conformation and Click here to see the residues together, and an between the two states.

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Alexander Berchansky, Michal Harel, Joel L. Sussman