Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer.

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.
Mesh Terms:
BRCA1 Protein, Basic-Leucine Zipper Transcription Factors, Breast Neoplasms, Cell Line, Tumor, Cell Nucleus, Crystallography, X-Ray, Fanconi Anemia Complementation Group Proteins, Female, Humans, Microscopy, Fluorescence, Mutation, Nuclear Proteins, Phosphopeptides, Protein Binding, Protein Structure, Tertiary, Transcription Factors, Transfection
Nat. Struct. Mol. Biol.
Date: Jun. 01, 2004
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