Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1

@article{Williams2001CrystalSO,
  title={Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1},
  author={R. S. Williams and Ruth Green and J N Mark Glover},
  journal={Nature Structural Biology},
  year={2001},
  volume={8},
  pages={838-842}
}
The C-terminal BRCT region of BRCA1 is essential for its DNA repair, transcriptional regulation and tumor suppressor functions. Here we determine the crystal structure of the BRCT domain of human BRCA1 at 2.5 Å resolution. The domain contains two BRCT repeats that adopt similar structures and are packed together in a head-to-tail arrangement. Cancer-causing missense mutations occur at the interface between the two repeats and destabilize the structure. The manner by which the two BRCT repeats… 
Insights into the Molecular Basis of Human Hereditary Breast Cancer from Studies of the BRCA1 BRCT Domain
  • J. Glover
  • Biology, Medicine
    Familial Cancer
  • 2005
TLDR
Structural and functional studies reveal that the N-terminal repeat is responsible for pSer binding while a groove at the interface of the two repeats recognizes the Phe, which indicates that missense variants identified in breast cancer screening programs often disrupt these interactions and these molecular defects may lead to an increased cancer risk.
Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer
TLDR
It is shown 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.
Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1
TLDR
Crystallographic and biochemical data suggest that the structural integrity of both binding sites is essential for peptide recognition, and the diminished peptide-binding capacity observed for cancer-associated BRCA1-BRCT variants may explain the enhanced cancer risks associated with these mutations.
Structural basis of phospho-peptide recognition by the BRCT domain of BRCA 1
The BRCT repeats in BRCA1 are essential for its tumour suppressor activity and function to interact with phosphorylated protein targets containing the sequence, pSer-XX-Phe. The structure of the
Interactions between BRCT repeats and phosphoproteins: tangled up in two.
TLDR
The C-terminal region of the breast-cancer-associated protein BRCA1 contains a pair of tandem BRCT repeats that are essential for the tumour suppressor function of the protein and may mediate phosphorylation-dependent protein-protein interactions in processes that are central to cell-cycle checkpoint and DNA repair functions.
Structural Consequences of a Cancer-causing BRCA1-BRCT Missense Mutation*
TLDR
Destabilization and global unfolding of the mutated BRCT domain at physiological temperatures explain the pleiotropic molecular and genetic defects associated with the BRCA1-M1775R protein.
Structure of the BRCT repeats of BRCA1 bound to a BACH1 phosphopeptide: implications for signaling.
TLDR
The crystal structure of the BRCT repeats of human BRCA1 bound to a phosphorylated BACH1 peptide at 2.3 A resolution is reported, suggesting an evolutionarily conserved function of phosphopeptide recognition.
Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor
TLDR
The crystal structure of the 53BP1BRCT tandem repeat in complex with the DNA‐binding domain of p53 shows that the BRCT tandem repeats pack together through a conserved interface that also involves the inter‐domain linker.
Linking up and interacting with BRCT domains.
TLDR
The protein-protein interactions involving three different inter-BRCT linker regions, those of DNA ligase IV (LigIV), Schizosaccharomyces pombe Crb2 and human 53BP1 are described.
Protein stability versus function: effects of destabilizing missense mutations on BRCA1 DNA repair activity.
TLDR
It is found that all of the mutations, regardless of how profound their destabilizing effects, retained some DNA repair activity and thereby partially rescued the chicken BRCA1 knockout, and the mutation R1699L, which disrupts the binding of phosphorylated proteins (but which is not destabilizing), was completely inactive.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 27 REFERENCES
Structure of an XRCC1 BRCT domain: a new protein–protein interaction module
TLDR
The first three‐dimensional structure and fold of a BRCT domain determined by X‐ray crystallography at 3.2 Å resolution is described and the established structure of an XRCC1 BRCT homodimer suggests potential protein–protein interaction sites for the complementaryBRCT domain in DNA ligase III.
BRCT domain interactions in the heterodimeric DNA repair protein XRCC1-DNA ligase III.
TLDR
Key amino acid residues mediating the interaction with DNA ligase III were identified here by targeted mutagenesis of the XRCC1 BRCT domain and provide the first demonstration of the surface contacts coordinating a functional BRCT-BRCT protein interaction.
The C-terminal (BRCT) Domains of BRCA1 Interact in Vivo with CtIP, a Protein Implicated in the CtBP Pathway of Transcriptional Repression*
TLDR
The results show that the BRCT domains interact in vivo with CtIP, a protein originally identified on the basis of its association with the CtBP transcriptional co-repressor, suggesting that BRCA1 regulates gene expression, at least in part, by modulating CtBP-mediated transcriptional repression.
From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair
TLDR
Sequence analysis using hydrophobic cluster analysis reveals the presence of 50 copies of the BRCT domain in 23 different proteins, including, in addition to BRCA1, 53BP1 and RAD9, XRCC1, RAD4, Ect2, REV1, Crb2, RAP1, terminal deoxynucleotidyltransferases (TdT) and three eukaryotic DNA ligases.
BRCA1 interacts with components of the histone deacetylase complex.
  • R. Yarden, L. Brody
  • Biology, Medicine
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
It is demonstrated that BRCA1 interacts with components of the histone deacetylase complex, and therefore may explain the involvement of BRC a1 in multiple processes such as transcription, DNA repair, and recombination.
BACH1, a Novel Helicase-like Protein, Interacts Directly with BRCA1 and Contributes to Its DNA Repair Function
TLDR
A BACH1 derivative, bearing a mutation in a residue that was essential for catalytic function in other helicases, interfered with normal double-strand break repair in a manner that was dependent on its BRCA1 binding function.
Binding of CtIP to the BRCT Repeats of BRCA1 Involved in the Transcription Regulation of p21 Is Disrupted Upon DNA Damage*
TLDR
It is suggested that the binding of the BRCT repeats of BRCA1 to CtIP/CtBP is critical in mediating transcriptional regulation of p21 in response to DNA damage.
Roles of BRCA1 and its interacting proteins
  • Chu‐Xia Deng, S. Brodie
  • Biology, Medicine
    BioEssays : news and reviews in molecular, cellular and developmental biology
  • 2000
TLDR
This review examines the understanding of the significance of the interactions between BRCA1 and other proteins, through which BRCa1 maintains genome integrity and represses tumor formation.
Crystal structure of NAD+‐dependent DNA ligase: modular architecture and functional implications
TLDR
The crystal structure of an NAD+‐dependent DNA ligase from Thermus filiformis, a 667 residue multidomain protein, has been determined by the multiwavelength anomalous diffraction (MAD) method and reveals highly modular architecture and a unique circular arrangement of its four distinct domains.
Genetic analysis of BRCA1 function in a defined tumor cell line.
TLDR
Retrovirally expressed, wild-type BRCA1 decreased the gamma radiation (IR) sensitivity and increased the efficiency of double-strand DNA break repair (DSBR) of the BRCa1-/- human breast cancer line, HCC1937, and this data constitute the basis for a BRC a1 functional assay and suggest that efficient repair of double strand DNA breaks is linked to BRCCancer1 tumor suppression function.
...
1
2
3
...