Mutations in Brca1 BRCT Domains
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| - | <StructureSection load='1T15_w_HybridPeptide.pdb' size='350' side='right' caption='Human BRCA1 (blue) complex with BRCA1 interacting protein C-terminal helicase 1 (olive) (PDB code [[1t15]])' scene='75/752201/Cv/5' pspeed='8'> | + | <StructureSection load='1T15_w_HybridPeptide.pdb' size='350' side='right' caption='Human BRCA1 (blue) complex with phosphoserine-containing BRCA1 interacting protein C-terminal helicase 1 (olive) (PDB code [[1t15]])' scene='75/752201/Cv/5' pspeed='8'> |
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.<ref>PMID: 15133502</ref> | 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.<ref>PMID: 15133502</ref> | ||
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References
- ↑ Clapperton JA, Manke IA, Lowery DM, Ho T, Haire LF, Yaffe MB, Smerdon SJ. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nat Struct Mol Biol. 2004 Jun;11(6):512-8. Epub 2004 May 9. PMID:15133502 doi:10.1038/nsmb775
