Structural Basis for BRCA1 Function in Breast Cancer
Abstract
The Breast Cancer Susceptibility gene 1 (BRCA1) encodes an 1863-amino acid protein that plays a central role in the pathogenesis of hereditary breast cancer. The BRCA1 protein contains an N-terminal RING finger and two C-terminal BRCT domains (BRCT1 and BRCT2), which are critical for BRCA1-mediated tumor suppression and are targets for cancer-causing mutations. The BRCA1 RING interacts with the RING domain of BARD1, another protein involved in breast cancer pathogenesis, and with the C-terminal domain of BAP1 (amino acids 598-729), a ubiquitin hydrolase that enhances BRCA1-mediated cell growth suppression, whereas the BRCA1 BRCT domains interact with the C-terminal region of BACH1 (amino acids 888-1063), a helicase- like protein that contributes to the BRCA1 DNA repair function. The present project focuses on the elucidation of the structural basis of the BRCA1 RING and BRCT domain interaction with the proteins BARD1, BAP1, and BACH1, using X-ray crystallography. In the first year of the award we completed the Tasks 1a, 1b, and 1c of the original Statement of Work. For the remaining years of the award, we propose to determine the crystal structures of the BRCA1 (residues 1-3 04)/BRAP1 (residues 598-729), BRCA1 (residues 1-304)/BARD 1 (residues 25-189), and BRCA1 (residues 1650-1863)/BACH1 (residues 888-1063) protein complexes.
Document Details
- Document Type
- Technical Report
- Publication Date
- Apr 01, 2003
- Accession Number
- ADA417605
Entities
People
- John A. Ladias
Organizations
- Beth Israel Deaconess Medical Center