Human CTP synthase filament structure reveals the active enzyme conformation

Abstract

The universally conserved enzyme CTP synthase (CTPS) forms filaments in bacteria and eukaryotes. In bacteria polymerization inhibits CTPS activity and is required for nucleotide homeostasis. Here we show that human CTPS polymerization increases catalytic activity. The cryoEM structures of bacterial and human CTPS filaments differ dramatically in overall architecture and in the conformation of the CTPS protomer, explaining the divergent consequences of polymerization on activity. The filament structure of human CTPS is the first full-length structure of the human enzyme and reveals a novel active conformation. The filament structures elucidate allosteric mechanisms of assembly and regulation that rely on a conserved conformational equilibrium. This may provide a mechanism for increasing human CTPS activity in response to metabolic state, and challenges the assumption that metabolic filaments are generally storage forms of inactivated enzymes. Allosteric regulation of CTPS polymerization by ligands likely represents a fundamental mechanism underlying assembly of other metabolic filaments.