Many mutations in the BRCA1 tumour suppressor gene that lead to an increased susceptibility to breast and ovarian cancers are located in the tandem BRCA1 carboxy-terminal (BRCT) domains. These domains are known to function together as a phosphoserine/phosphothreonine-binding module, but how do they recognize phosphopeptides? And, might cancer-causing mutations in these domains specifically disrupt protein–protein interactions?
In Nature Structural and Molecular Biology, papers from Smerdon, Yaffe and colleagues and the Glover group now describe crystal structures of the BRCA1 BRCT domains bound to phosphopeptides that contain the pSer-X-X-Phe recognition motif (where pSer represents phosphoserine and X represents any amino acid). Both papers show that each BRCT domain forms a compact unit and that the phosphopeptides bind to a groove between these domains. The pSer residue of the motif binds to a basic pocket in the amino-terminal BRCT domain, whereas the Phe binds to a hydrophobic pocket between the domains. Smerdon, Yaffe and colleagues showed that a set of cancer-related BRCT mutations disrupt BRCA1–phosphopeptide interactions in vitro and BRCA1–phosphoprotein binding in vivo. The Glover group also showed that a large set of cancer-causing BRCT mutations disrupt phosphopeptide binding by using peptide-binding assays and by determining the crystal structures of two BRCT variants. These papers have therefore shown that a specific reduction in the phosphopeptide-binding ability of the BRCT domains, rather than a general disruption of the BRCT fold, might explain the increased cancer risks that are associated with BRCT mutations. REFERENCES Clapperton, J. A. et al. Structure and mechanism of BRCA1 BRCT domain recognition of phosphorylated BACH1 with implications for cancer. Nature Struct. Mol. Biol. 9 May 2004 (doi:10.1038/nsmb775) Williams, R. S. et al. Structural basis of phosphopeptide recognition by the BRCT domain of BRCA1. Nature Struct. Mol. Biol. 9 May 2004 (doi:10.1038/nsmb776)
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