Nature Structural & Molecular Biology pp 512 - 518 and 519 - 525

Most of the inherited, early-onset breast cancers result from mutations within the C-terminal region of the BRCA1 protein. In the June issue of Nature Structural & Molecular Biology, two structural studies reveal how such mutations can affect the function of BRCA1, leading to cancer.

Breast cancer is one of the most common types of cancer in women. Among the ~180,000 women affected each year, ~5% are due to inherited germline mutations in the breast cancer susceptibility gene product, BRCA1. BRCA1 plays a number of important roles in the cell including the response to DNA damage.

The C-terminal region of BRCA1 contains tandem repeats called BRCT domains that are generally thought to function as protein-protein interaction modules. Recent studies have shown that these repeats recognize phosphoserine or phosphothreonine (pSer or pThr) peptides, suggesting that some of the interactions of BRCA1 with other proteins may be regulated by protein phosphorylation.

Now, two groups have determined the structures of tandem BRCT repeats bound to phosphopeptides. Yaffe (Massachusetts Institute of Technology, USA) and coworkers determined the crystal structure of this repeat domain bound to a phosphopeptide derived from Bach1, a known partner of BRCA1. The structure explains why tandem BRCT repeats, rather than single BRCT domains, are required for phosphopeptide binding since residues from both repeats are important for peptide recognition. They further showed that a set of disease-related mutations disrupted BRCA1-substrate binding in vitro and in vivo.

Glover (University of Alberta, Canada) and coworkers determined the structure of the BRCT repeat bound to another peptide containing a high affinity-binding motif (pSer-X-X-Phe). They identified a conserved pSer binding pocket on BRCT as well as a hydrophobic groove between the two BRCT repeats that recognizes the Phe. These authors further examined the phosphopeptide binding properties of a large set of clinically derived BRAC1 BRCT variants and solved the structures of two BRCT repeats carrying missense mutations. The results indicate that the peptide-binding surface of BRCA1 is essential for its tumor suppression function.

Together these studies suggest that the majority of mutations that map to BRCT disrupt phosphopeptide binding or perturb the interface between BRCT repeats that forms the phosphopeptide-binding groove. In so doing, such mutations lead to the elevated cancer risks associated with these variants.