Mutations in Brca1 BRCT Domains
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| - | <StructureSection load='1T15_w_HybridPeptide.pdb' size=' | + | <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> |
<scene name='75/752201/Cv/4'>Brca1 BRCT domains in complex with the phosphorylated interacting region from Bach1 Helicase</scene>. | <scene name='75/752201/Cv/4'>Brca1 BRCT domains in complex with the phosphorylated interacting region from Bach1 Helicase</scene>. | ||
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</jmolLink> | </jmolLink> | ||
</jmol> between the two states. | </jmol> between the two states. | ||
| - | *<scene name='75/752201/G1788v/ | + | *<scene name='75/752201/G1788v/4'>Mutation G1788V:</scene> |
<jmol> | <jmol> | ||
<jmolLink> | <jmolLink> | ||
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=== Very severe pathogenic mutations === | === Very severe pathogenic mutations === | ||
| - | *<scene name='75/752201/R1899w/ | + | *<scene name='75/752201/R1899w/4'>Mutation R1699W:</scene> |
<jmol> | <jmol> | ||
<jmolLink> | <jmolLink> | ||
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</jmolLink> | </jmolLink> | ||
</jmol> between the two states. This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; '''interaction lost with BRCA1 interacting protein C-terminal helicase 1'''. | </jmol> between the two states. This mutation causes saltbridges lost, hydrogen bonds lost, overpacking, clashes; '''interaction lost with BRCA1 interacting protein C-terminal helicase 1'''. | ||
| - | *<scene name='75/752201/A1708e/ | + | *<scene name='75/752201/A1708e/4'>Mutation A1708E:</scene> |
<jmol> | <jmol> | ||
<jmolLink> | <jmolLink> | ||
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</jmolLink> | </jmolLink> | ||
</jmol> between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase. | </jmol> between the two states. This mutation causes interference with phosphorylated interacting region from Bach1 Helicase. | ||
| - | *<scene name='75/752201/M1775k/ | + | *<scene name='75/752201/M1775k/5'>Mutation M1775K:</scene> |
<jmol> | <jmol> | ||
<jmolLink> | <jmolLink> | ||
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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
