STRUCTURE OF AN XRCC1 BRCT DOMAIN - A NEW PROTEIN-PROTEIN INTERACTIONMODULE

The BRCT domain (BRCA1 C-terminus), first identified in the breast can cer suppressor protein BRCA1, is an evolutionarily conserved protein-p rotein interaction region of similar to 95 amino acids found in a larg e number of proteins involved in DNA repair, recombination and cell cy cle control, Here we describe the first three-dimensional structure an d fold of a BRCT domain determined by X-ray crystallography at 3.2 Ang strom resolution. The structure has been obtained from the C-terminal region of the human DNA repair protein XRCC1, and comprises a four-str anded parallel beta-sheet surrounded by three alpha-helices, which for m an autonomously folded domain. The compact XRCC1 structure explains the observed sequence homology between different BRCT motifs and provi des a framework for modelling other BRCT domains, Furthermore, the est ablished structure of an XRCC1. BRCT homodimer suggests potential prot ein-protein interaction sites for the complementary BRCT domain in DNA ligase III, since these two domains form a stable heterodimeric compl ex, Based on the XRCC1 BRCT structure, we have constructed a model for the C-terminal BRCT domain of BRCA1, which frequently is mutated in f amilial breast and ovarian cancer. The model allows insights into the effects of such mutations on the fold of the BRCT domain.