Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1
Open accessAbstract
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).”
From The BRCA1-Interacting Protein Abraxas Is Required for Genomic Stability and Tumor Suppression (2014) · cites this paper as 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
- green
- hdl.handle.net
- Licence
- www.springer.com/tdm (tdm)
- 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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