Join us for the latest instalment of the Structural Biology Seminar Series on 8 November. Dr Timm Maier (University of Basel) will deliver a talk entitled ‘The structural basis for regulation of acetyl-CoA carboxylase 1′.
Abstract
The de novo biosynthesis of fatty acids in mammals is carried out by the combined action of two giant multienzymes. First, in a rate-limiting and committed step, acetyl-CoA carboxylase 1 (ACC) catalyses the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. Second, fatty acid synthase (FAS) elongates an acetyl-moiety from acetyl-CoA by iterative decarboxylative condensation with malonyl groups of malonyl-CoA and subsequent modification of the intermediate. ACC and FAS transcription is regulated by mTORC signalling and sterol sensing. Overexpression of both proteins is observed in cancers and during replication of many viruses.
ACC serves as a key hub for short term control of fatty acid and lipid biosynthesis. It is controlled via multi-site phosphorylation, allosteric feed-forward activation by citrate and feedback inhibition by palmitoyl-CoA as well as by regulatory protein-protein interactions. ACC regulation is closely linked to polymerization, and filaments are the most active form of ACC. By combining functional assays and cryoEM analysis we reveal the structural basis for ACC activity control by formation of distinct types of active and inactive filaments induced by allosteric control or protein-protein interactions.