title: Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1.
abstract: The tandem BRCA1 C-terminal (BRCT) domains are phospho-serine/threonine recognition modules essential for the function of BRCA1. Recent studies suggest that acetyl-CoA carboxylase 1 (ACC1), an enzyme with crucial roles in de novo fatty acid biosynthesis and lipogenesis and essential for cancer cell survival, may be a novel binding partner for BRCA1, through interactions with its BRCT domains. We report here the crystal structure at 3.2 A resolution of human BRCA1 BRCT domains in complex with a phospho-peptide from human ACC1 (p-ACC1 peptide, with the sequence 1258-DSPPQ-pS-PTFPEAGH-1271), which provides molecular evidence for direct interactions between BRCA1 and ACC1. The p-ACC1 peptide is bound in an extended conformation, located in a groove between the tandem BRCT domains. There are recognizable and significant structural differences to the binding modes of two other phospho-peptides to these domains, from BACH1 and CtIP, even though they share a conserved pSer-Pro-(Thr/Val)-Phe motif. Our studies establish a framework for understanding the regulation of lipid biosynthesis by BRCA1 through its inhibition of ACC1 activity, which could be a novel tumor suppressor function of BRCA1.
authors.affiliation: Department of Biological Sciences, Columbia University, New York City, New York 10027, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
mesh_terms: D000123:Acetyltransferases / Q000737:chemistry*; D020816:Amino Acid Motifs; D019313:BRCA1 Protein / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary
chemical_list: D019313:BRCA1 Protein; D008055:Lipids; D010455:Peptides; D000123:Acetyltransferases; C055210:aminoglycoside N1-acetyltransferase