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

Shen Y, Tong L
Biochemistry 47 5767-73 (2008)
Cited: 36 times
EuropePMC logo PMID: 18452305

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.

Reviews - 3coj mentioned but not cited (3)

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  1. Structure and function of biotin-dependent carboxylases. Tong L. Cell Mol Life Sci 70 863-891 (2013)
  2. BRCT domains: easy as one, two, three. Leung CC, Glover JN. Cell Cycle 10 2461-2470 (2011)
  3. Structures, functions, and mechanisms of filament forming enzymes: a renaissance of enzyme filamentation. Park CK, Horton NC. Biophys Rev 11 927-994 (2019)
  4. BRCT domains: A little more than kin, and less than kind. Gerloff DL, Woods NT, Farago AA, Monteiro AN. FEBS Lett 586 2711-2716 (2012)
  5. Chemical genetics of acetyl-CoA carboxylases. Zu X, Zhong J, Luo D, Tan J, Zhang Q, Wu Y, Liu J, Cao R, Wen G, Cao D. Molecules 18 1704-1719 (2013)
  6. Structural mechanisms underlying signaling in the cellular response to DNA double strand breaks. Mermershtain I, Glover JN. Mutat Res 750 15-22 (2013)
  7. BRCA1-A and BRISC: Multifunctional Molecular Machines for Ubiquitin Signaling. Rabl J. Biomolecules 10 E1503 (2020)
  8. Phosphorylation-dependent assembly of DNA damage response systems and the central roles of TOPBP1. Day M, Oliver AW, Pearl LH. DNA Repair (Amst) 108 103232 (2021)
  9. Regulation of tumor metabolism by post translational modifications on metabolic enzymes. Sawant Dessai A, Kalhotra P, Novickis AT, Dasgupta S. Cancer Gene Ther 30 548-558 (2023)
  10. Targeting acetyl-CoA carboxylase 1 for cancer therapy. Yu Y, Nie Q, Wang Z, Di Y, Chen X, Ren K. Front Pharmacol 14 1129010 (2023)
  11. The Many Faces of Lipids in Genome Stability (and How to Unmask Them). Moriel-Carretero M. Int J Mol Sci 22 12930 (2021)

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