Structural Basis for BRCA1 Function in Breast Cancer
Abstract
The Breast Cancer Susceptibility gene 1 (BRCA1) encodes an 1863-amino acid protein that has important functions in cell cycle checkpoint control and DNA repair and plays a central role in the pathogenesis of breast cancer. Two tandem BRCA1 C-terminal domains (BRCT1 and BRCT2) are essential for the tumor suppression activity of BRAC1 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 present project has resulted in the structure determination of the BRCA1 BRCT domains complexed with the phopshopeptide PTRVSpSPVFGAT from human CtIP (residues 322-333) at 2.5 A resolution, using X-ray crystallography. 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 5-fold lower affinity of BRCA1 for CtIP than BACH1, as determined by isothermal titration calorimetry. The information obtained from these experiments has elucidated the mechanisms underlying regulation of BRCA1 by BACH1 and CtIP and has revealed the molecular changes induced by cancer-causing mutations in the BRCA1 domains that affect their interaction with these proteins.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2005
- Accession Number
- ADA436887
Entities
People
- John A. Ladias
Organizations
- Beth Israel Deaconess Medical Center