NMR Structural Investigations of BRCA1
EMSL Project ID
2178
Abstract
This project is aimed at gaining structural insights into the biological function and dysfunction of the breast cancer susceptibility protein known as BRCA1. Though the biological role of BRCA1 is not yet clearly understood, accumulating evidence implicates the involvement of BRCA1 in the cellular response to DNA damage in addition to other postulated functions in homologous recombination and transcriptional regulation. A full understanding of the cellular role of BRCA1 requires a detailed understanding of both the function and the structure of the protein and its interacting partners. BRCA1 is a large and complicated protein which is undoubtedly comprised of a multiplicity of functional domains. We are focusing initially on the N-terminal region of BRCA1, which contains a conserved pattern of cysteine and histidine residues found in the RING-finger family of proteins. The RING-finger is a Zn+2-binding motif found in a wide variety of proteins that are diverse both in function and origin. We have found that the RING-finger motif in BRCA1 is part of a larger N-terminal structural domain.1 This region is the site of numerous mutations found in families genetically predisposed to breast and ovarian cancer. Encompassing only 110 residues, this remarkable domain of BRCA1 has been found to interact with at least three different unrelated protein partners: 1) the N-terminal RING domain of BARD1, a nuclear protein found to colocalize with BRCA1 in vivo, 2) the C-terminal region of BAP1, a putative ubiquitin hydrolase, and 3) ATF1, a member of the family of basic zipper transcription factors. In addition, the BRCA1 RING domain also has been found to contain a functional nuclear export sequence which permits BRCA1 to shuttle between the nucleus and the cytoplasm.
Project Details
Project type
Capability Research
Start Date
2001-06-13
End Date
2001-09-04
Status
Closed
Released Data Link
Team
Principal Investigator
Related Publications
Brzovic PS, JR Keeffe, H Nishikawa, K Miyamoto, D Fox, M Fukuda, T Ohta, and RE Klevit. 2003. "Binding and Recognition in the Assembly of an Active BRCA1/BARD1 Ubiquitin-Ligase Complex ." Proceedings of the National Academy of Sciences of the United States of America 100(10):5646-5651.