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Structural basis for regulation of human acetyl-CoA carboxylase

Hunkeler, Moritz and Hagmann, Anna and Stuttfeld, Edward and Chami, Mohamed and Guri, Yakir and Stahlberg, Henning and Maier, Timm. (2018) Structural basis for regulation of human acetyl-CoA carboxylase. Nature, 558 (7710). pp. 470-474.

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Official URL: https://edoc.unibas.ch/64708/

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Abstract

Acetyl-CoA carboxylase catalyses the ATP-dependent carboxylation of acetyl-CoA, a rate-limiting step in fatty acid biosynthesis; 1,2; . 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; 1,3; . ACC1 is regulated by a complex interplay of phosphorylation, binding of allosteric regulators and protein-protein interactions, which is further linked to filament formation; 1,4-8; . These filaments were discovered in vitro and in vivo 50 years ago; 7,9,10; , 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Maier)
05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Stahlberg)
UniBasel Contributors:Maier, Timm and Chami, Mohamed and Guri, Yakir and Stahlberg, Henning
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:27 Apr 2020 10:10
Deposited On:27 Apr 2020 10:10

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