Human CTP synthase filament structure reveals the active enzyme conformation.

TitleHuman CTP synthase filament structure reveals the active enzyme conformation.
Publication TypeJournal Article
Year of Publication2017
AuthorsLynch, EM, Hicks, DR, Shepherd, M, Endrizzi, JA, Maker, A, Hansen, JM, Barry, RM, Gitai, Z, Baldwin, EP, Kollman, JM
JournalNat Struct Mol Biol
Date Published2017 Jun
KeywordsCarbon-Nitrogen Ligases, Cryoelectron Microscopy, Crystallography, X-Ray, Humans, Macromolecular Substances, Models, Molecular, Protein Conformation, Protein Multimerization

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 for human CTPS, polymerization increases catalytic activity. The cryo-EM structures of bacterial and human CTPS filaments differ considerably in overall architecture and in the conformation of the CTPS protomer, explaining the divergent consequences of polymerization on activity. The structure of human CTPS filament, the first structure of the full-length human enzyme, reveals a novel active conformation. The filament structures elucidate allosteric mechanisms of assembly and regulation that rely on a conserved conformational equilibrium. The findings may provide a mechanism for increasing human CTPS activity in response to metabolic state and challenge the assumption that metabolic filaments are generally storage forms of inactive enzymes. Allosteric regulation of CTPS polymerization by ligands likely represents a fundamental mechanism underlying assembly of other metabolic filaments.

Alternate JournalNat. Struct. Mol. Biol.
PubMed ID28459447
PubMed Central IDPMC5472220
Grant ListR01 GM118396 / GM / NIGMS NIH HHS / United States