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Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

R Scott Williams1, Megan S Lee, D Duong Hau

  • 1Department of Biochemistry, University of Alberta, Edmonton, Alberta, T6G 2H7, Canada.

Nature Structural & Molecular Biology
|May 11, 2004
PubMed

Insights

The BRCA1 BRCT repeats bind to specific phosphopeptides, crucial for tumor suppression. Mutations in these repeats impair binding, potentially explaining increased cancer risk.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Cancer Biology

Background:

  • The BRCA1 protein functions as a tumor suppressor.
  • BRCA1's tumor suppressor activity relies on its BRCT repeats.
  • BRCT repeats recognize phosphorylated motifs (pSer-X-X-Phe) in target proteins.

Purpose of the Study:

  • To elucidate the structural basis of BRCA1 BRCT repeat interaction with phosphopeptides.
  • To understand how cancer-associated mutations in BRCA1 BRCT affect phosphopeptide binding.

Main Methods:

  • X-ray crystallography to determine the structure of BRCA1 BRCT repeats bound to a phosphopeptide.
  • Biochemical assays to assess peptide binding affinity and specificity.

Main Results:

  • The structure reveals distinct binding sites within the tandem BRCT repeats: a phosphoserine-binding pocket in the N-terminal repeat and a hydrophobic groove for phenylalanine recognition at the interface.
  • Both binding sites are structurally integral and essential for effective phosphopeptide recognition.
  • Cancer-associated BRCA1-BRCT variants exhibit reduced phosphopeptide-binding capacity.

Conclusions:

  • The structural insights explain the molecular mechanism of BRCA1 BRCT-phosphopeptide interaction.
  • Impaired phosphopeptide binding due to mutations in BRCA1 BRCT repeats likely contributes to the loss of tumor suppressor function and increased cancer susceptibility.

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