Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1

Biochemistry. 2008 May 27;47(21):5767-73. doi: 10.1021/bi800314m. Epub 2008 May 2.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acetyltransferases / chemistry*
  • Amino Acid Motifs
  • BRCA1 Protein / chemistry*
  • Crystallography, X-Ray
  • Humans
  • Kinetics
  • Lipids / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Peptides / chemistry
  • Phosphorylation
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary


  • BRCA1 Protein
  • Lipids
  • Peptides
  • Acetyltransferases
  • aminoglycoside N1-acetyltransferase