Structural basis for regulation of human acetyl-CoA carboxylase

Nature. 2018 Jun;558(7710):470-474. doi: 10.1038/s41586-018-0201-4. Epub 2018 Jun 13.


Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis1,2. Eukaryotic acetyl-CoA carboxylases are large, homodimeric multienzymes. Human acetyl-CoA carboxylase occurs in two isoforms: the metabolic, cytosolic ACC1, and ACC2, which is anchored to the outer mitochondrial membrane and controls fatty acid β-oxidation1,3. ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein-protein interactions, which is further linked to filament formation1,4-8. These filaments were discovered in vitro and in vivo 50 years ago7,9,10, but the structural basis of ACC1 polymerization and regulation remains unknown. Here, we identify distinct activated and inhibited ACC1 filament forms. We obtained cryo-electron microscopy structures of an activated filament that is allosterically induced by citrate (ACC-citrate), and an inactivated filament form that results from binding of the BRCT domains of the breast cancer type 1 susceptibility protein (BRCA1). While non-polymeric ACC1 is highly dynamic, filament formation locks ACC1 into different catalytically competent or incompetent conformational states. This unique mechanism of enzyme regulation via large-scale conformational changes observed in ACC1 has potential uses in engineering of switchable biosynthetic systems. Dissecting the regulation of acetyl-CoA carboxylase opens new paths towards counteracting upregulation of fatty acid biosynthesis in disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyl-CoA Carboxylase / chemistry*
  • Acetyl-CoA Carboxylase / metabolism
  • Acetyl-CoA Carboxylase / ultrastructure*
  • Animals
  • BRCA1 Protein / chemistry
  • BRCA1 Protein / pharmacology
  • Biopolymers / chemistry
  • Biopolymers / metabolism
  • Cell Line
  • Citric Acid / pharmacology
  • Cryoelectron Microscopy*
  • Humans
  • Models, Molecular
  • Polymerization / drug effects
  • Protein Domains / drug effects
  • Protein Structure, Quaternary / drug effects
  • Spodoptera
  • Structure-Activity Relationship


  • BRCA1 Protein
  • Biopolymers
  • Citric Acid
  • ACACA protein, human
  • Acetyl-CoA Carboxylase