NMR Structural Investigations of BRCA1
EMSL Project ID
2612d
Abstract
The breast and ovarian cancer tumor suppressor protein, BRCA1, supports a number of fundamental cellular processes. Its absence during embryogenesis is lethal. Loss of function in proliferating breast or ovarian epithelial cells can result in the development of cancer. A growing body of literature suggests that BRCA1 interacts with at least 25 different macromolecules to function in processes such as the cellular response to DNA damage, homologous recombination, transcriptional regulation, and, more recently, ubiquitination. A complete picture 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. This proposal focuses on the N-terminal region of BRCA1, which contains a highly conserved RING finger motif. Our previous work studying the N-terminal region of BRCA1 has shown that the BRCA1 RING-finger motif (~55 residues) is part of a larger N-terminal structural domain. Encompassing only 110 residues, this remarkable region of BRCA1 is the site of numerous mutations found in families genetically predisposed to breast and ovarian cancer. A number of different protein partners have been identified which specifically interact with this domain of BRCA1. These proteins include the N-terminal RING domain of BARD1, a nuclear protein found to colocalize with BRCA1 in vivo, and the C-terminal region of BAP1, a putative ubiquitin hydrolase. Of particular interest is the recent demonstration that the BRCA1 RING domain exhibits activity as an E3 ubiquitin ligase. Protein ubiquitination provides a powerful regulatory mechanism for controlling pathways that include cell-cycle progression and transcriptional regulation. In their role as E3-ligases, RING domains are thought to facilitate the specificity of ubiquitination reactions by binding both a ubiquitin conjugating enzyme (E2) covalently activated with ubiquitin and specific proteins targeted for ubiquitination. The RING domain of BRCA1 has been shown to have E3 ligase activity only in conjunction with the E2 enzyme UbcH5c and only when complexed with the RING domain of BARD1. Thus, structural characterization of the interaction of BRCA1 with its various protein partners promises to yield important insight regarding the function of the BRCA1 RING domain and also further our understanding underlying the deleterious structural and functional consequences of known cancer pre-disposing mutations.
Project Details
Project type
Capability Research
Start Date
2006-04-06
End Date
2007-05-21
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
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