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.
Clapperton
Julie A
JA
National Institute for Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Manke
Isaac A
IA
Lowery
Drew M
DM
Ho
Timmy
T
Haire
Lesley F
LF
Yaffe
Michael B
MB
Smerdon
Stephen J
SJ
D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050976:Basic-Leucine Zipper Transcription Factors; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry; D018360:Crystallography, X-Ray; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D010748:Phosphopeptides / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
C102108:BACH1 protein, human; D019313:BRCA1 Protein; D050976:Basic-Leucine Zipper Transcription Factors; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D010748:Phosphopeptides; D014157:Transcription Factors