Cited by 230BRCA gene mutations in cancerDNA Repair MechanismsCancer-related Molecular Pathways

Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1

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Williams, R Scott, Lee, Megan S, Hau, D Duong, Glover, J N Mark·2004·Nature Structural & Molecular Biology

Abstract

The BRCT repeats in BRCA1 are essential for its tumor suppressor activity and interact with phosphorylated protein targets containing the sequence pSer-X-X-Phe, where X indicates any residue. The structure of the tandem BRCA1 BRCT repeats bound to an optimized phosphopeptide reveals that the N-terminal repeat harbors a conserved BRCT phosphoserine-binding pocket, while the interface between the repeats forms a hydrophobic groove that recognizes the phenylalanine. Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition. The diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.

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  • The phenylalanine residue in the pSPxF motif is essential for recognition of the motif by BRCA1 BRCT domains.

    “Structural and biochemical analysis of BRCA1 BRCT domains bound to optimized phosphopeptides has revealed that the phenylalanine residue in the pSPxF motif is essential for the recognition of this motif by the BRCT domains (Rodriguez et al., 2003; Shiozaki et al., 2004; Williams et al., 2004).”

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Authors
Williams, R. S., Lee, M. S., Hau, D. D., & Glover, J. N. M.
Affiliations
University of Alberta (CA)
Corresponding author
Glover, J N Mark
Venue
Nature Structural & Molecular Biology
Published
2004-05-09
Volume
11
Issue
6
Pages
519-525
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W1981864085
Cited by
230
References
36
Citations by year
2026: 3 · 2025: 7 · 2024: 5 · 2023: 14 · 2022: 6 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 3 · 2016: 6 · 2015: 6 · 2014: 16 · 2013: 13 · 2012: 13
FWCI
9.29
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • TSpace (University of Toronto) (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
BRCA1, BRCT domain, phosphopeptide recognition, protein phosphorylation, tumor suppressor, protein-peptide interactions, tandem repeats
MeSH terms
Amino Acid Sequence, Binding Sites, Breast Neoplasms, Female, Humans, Mutation, Phosphopeptides, Protein Binding, Transfection, Molecular Structure, Protein Structure, Tertiary, Crystallography, X-Ray, BRCA1 Protein, Cell Line, Tumor

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