1Y98: Structure Of The Brct Repeats Of Brca1 Bound To A Ctip Phosphopeptide

Citation:
Abstract
The breast and ovarian tumor suppressor BRCA1 has important functions in cell cycle checkpoint control and DNA repair. Two tandem BRCA1 C-terminal (BRCT) domains are essential for the tumor suppression activity of BRCA1 and interact in a phosphorylation-dependent manner with proteins involved in DNA damage-induced checkpoint control, including the DNA helicase BACH1 and the CtBP-interacting protein (CtIP). The crystal structure of the BRCA1 BRCT repeats bound to the PTRVSpSPVFGAT phosphopeptide corresponding to residues 322-333 of human CtIP was determined at 2.5 A resolution. The peptide binds to a cleft formed by the interface of the two BRCTs in a two-pronged manner, with phospho-Ser327 and Phe330 anchoring the peptide through extensive contacts with BRCA1 residues. Several hydrogen bonds and salt bridges that stabilize the BRCA1-BACH1 complex are missing in the BRCA1-CtIP interaction, offering a structural basis for the approximately 5-fold lower affinity of BRCA1 for CtIP compared to that of BACH1, as determined by isothermal titration calorimetry. Importantly, the side chain of Arg1775 in the cancer-associated BRCA1 mutation M1775R sterically clashes with the phenyl ring of CtIP Phe330, disrupting the BRCA1-CtIP interaction. These results provide new insights into the molecular mechanisms underlying the dynamic selection of target proteins involved in DNA repair and cell cycle control by BRCA1 and reveal how certain cancer-associated mutations affect these interactions.
PDB ID: 1Y98Download
MMDB ID: 34659
PDB Deposition Date: 2004/12/14
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.5  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1Y98: dimeric; determined by author and by software (PISA)
Molecular Components in 1Y98
Label Count Molecule
Proteins (2 molecules)
1
Breast Cancer Type 1 Susceptibility Protein(Gene symbol: BRCA1)
Molecule annotation
1
Ctip Phosphorylated Peptide
Molecule annotation
Chemicals (2 molecules)
1
1
2
1
* Click molecule labels to explore molecular sequence information.

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