Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA， a rate-limiting step in fatty acid biosynthesis. 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-oxidation. ACC1 is regulated by a complex interplay of phosphorylation， binding of allosteric regulators and protein-protein interactions， which is further linked to filament formation. These filaments were discovered in vitro and in vivo 50 years ago， but the structural basis of ACC1 polymerization and regulation remains unkn... More
Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA， a rate-limiting step in fatty acid biosynthesis. 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-oxidation. ACC1 is regulated by a complex interplay of phosphorylation， binding of allosteric regulators and protein-protein interactions， which is further linked to filament formation. These filaments were discovered in vitro and in vivo 50 years ago， 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.
