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2024

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West Lake University Hu Qi/Shi Yigong and other cooperation in the latest Science sub-issue

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Human acetyl-CoA (CoA) carboxylases (ACCs) catalyze the carboxylation of acetyl-CoA, the rate-limiting step in fatty acid synthesis. The molecular mechanisms of the dynamic organization of ACCs are largely unknown.

On October 9, 2024, Hu Qi and Shi Yigong of West Lake University were inScience AdvancesPublished online entitled“Filament structures unveil the dynamic organization of human acetyl-CoA carboxylase”The research paper,The studyThe cryo-electron microscopy (EM) structure of human ACC1 in its inactive state, which forms a unique filament structure and forms a complex with acetyl-CoA, was determined.

The study also determined the cryo-electron microscopic structure of human ACC1 activated by dephosphorylation and citrate treatment with a resolution of 2.55 Å. Notably, when acetyl-CoA is absent, the covalently linked biotin binds to a site that is further away from the acetyl-CoA binding site, suggesting a potential synergy between biotin binding and acetyl-CoA binding.These findings provide insights into the structural dynamics and regulatory mechanisms of human ACCs.

 

Acetyl-CoA (CoA) carboxylases (ACCs) in the family of bio-independent carboxylases (BDCs) catalyze the reaction between acetyl-CoA and bicarbonate to produce malonyl-CoA. This reaction, known as carboxylation of acetyl-CoA, is the first and rate-limiting step in fatty acid synthesis, and thus plays a crucial role in lipid metabolism.

ACC is ubiquitous in organisms ranging from prokaryotes to eukaryotes. Prokaryotic ACC is a multi-subunit complex composed of biotin carboxyl carrier protein (BCCP), biotin carboxylase (BC), and carboxyl transferase (CT) subunits.The BCCP subunit is first biotinylated on a lysine residue of the/V MKM motif, catalyzed by biotin-protein ligase. The BCCP subunit then binds to the BC subunit. The covalently bound biotin is carboxylated with bicarbonate as the carboxyl donor and adenosine 5 '-triphosphate (ATP) as the energy source.Finally, the BCCP subunit relocates to the CT subunit, and the carboxylated biotin transfers its carboxyl group to acetyl-CoA, completing the entire catalytic process. Unlike prokaryotic ACCs, eukaryotic ACCs are single-chain proteins, with the BC, BCCP, and CT domains arranged sequentially. In each eukaryotic ACC there is a BC-CT interaction domain (BT) between the BC and BCCP domains and a central domain (CD) between the BCCP and CT domains.

Phosphorylation leads to inactivation of human ACCs. Citrate, a key metabolite in the citric acid cycle, activates human ACCs by binding to ACCs and regulating the organization of different domains within the enzyme. Dephosphorylation and citrate binding have additive effects in activating human ACCs. In the presence of citrate, dephosphorylated ACC1 forms filaments (ACC-citrate filaments). The cryo-electron microscopy (EM) structure of ACC-citrate filaments, with a resolution of 5.4 Å, reveals that the filaments (filaments) are formed by CD domain-mediated assembly of ACC1 dimers. The structure of the ACC1 homodimer in ACC-citrate silk is similar to that of the ScACC homodimer, suggesting that eukaryotic ACCs have a conserved working mechanism.

In this study, the authors purified endogenously expressed human ACC from Expi 293F cells and identified a previously unidentified ACC filament (ACC-inact filaments,, where "inact" refers to the inactive state of ACC) by incubating the purified ACC with a substrate and determining its cryo-electron microscopic structure. The cryo-electron microscopic structure of ACC-citric acid filaments was determined at an improved resolution. Structural analysis showed that ACC1 was in an inactive conformation in ACC-intact filaments.This study indicates that the organization of human ACC is highly dynamic, with its dynamics being regulated by various modulators.

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