3COJ

Crystal Structure of the BRCT Domains of Human BRCA1 in Complex with a Phosphorylated Peptide from Human Acetyl-CoA Carboxylase 1

Summary for 3COJ

• Entry DOI: 10.2210/pdb3coj/pdb
• Related: 1T15 1T29 1T2V 1Y98 2AZM
• Descriptor: Breast cancer type 1 susceptibility protein, Acetyl-CoA carboxylase 1 (2 entities in total)
• Functional Keywords: breast cancer, ovarian cancer, fatty acid biosynthesis, lipid synthesis, obesity, protein-peptide complex, protein protein interaction, anti-oncogene, cell cycle, disease mutation, dna damage, dna repair, dna-binding, metal-binding, nucleus, phosphoprotein, zinc-finger, alternative promoter usage, atp-binding, biotin, ligase, manganese, multifunctional enzyme, nucleotide-binding, antitumor protein-ligase complex, antitumor protein/ligase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus . Isoform 3: Cytoplasm. Isoform 5: Cytoplasm : P38398; Cytoplasm: Q13085
• Total number of polymer chains: 16
• Total formula weight: 225945.22

Authors

Shen, Y.,Tong, L. (deposition date: 2008-03-28, release date: 2008-05-27, Last modification date: 2023-08-30)

Primary citation

Shen, Y.,Tong, L.
Structural evidence for direct interactions between the BRCT domains of human BRCA1 and a phospho-peptide from human ACC1
Biochemistry, 47:5767-5773, 2008

PubMed 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.

PubMed: 18452305
DOI: 10.1021/bi800314m

Experimental method

X-RAY DIFFRACTION (3.21 Å)