Abstract
Acetyl-CoA carboxylases (ACCs) catalyse the committed step in fatty-acid biosynthesis: the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. They are important regulatory hubs for metabolic control and relevant drug targets for the treatment of the metabolic syndrome and cancer. Eukaryotic ACCs are single-chain multienzymes characterized by a large, non-catalytic central domain (CD), whose role in ACC regulation remains poorly characterized. Here we report the crystal structure of the yeast ACC CD, revealing a unique four-domain organization. A regulatory loop, which is phosphorylated at the key functional phosphorylation site of fungal ACC, wedges into a crevice between two domains of CD. Combining the yeast CD structure with intermediate and low-resolution data of larger fragments up to intact ACCs provides a comprehensive characterization of the dynamic fungal ACC architecture. In contrast to related carboxylases, large-scale conformational changes are required for substrate turnover, and are mediated by the CD under phosphorylation control.
Highlights
Acetyl-CoA carboxylases (ACCs) catalyse the committed step in fatty-acid biosynthesis: the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA
CDC1/CDC2 share a common fold; they are composed of six-stranded b-sheets flanked on one side by two long, bent helices inserted between strands b3/b4 and b4/b5
Altogether, the architecture of fungal ACC is based on the central dimeric CT domain (Fig. 4d)
Summary
Acetyl-CoA carboxylases (ACCs) catalyse the committed step in fatty-acid biosynthesis: the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA. Biotin-dependent acetyl-CoA carboxylases (ACCs) are essential enzymes that catalyse the ATP-dependent carboxylation of acetyl-CoA to malonyl-CoA This reaction provides the committed activated substrate for the biosynthesis of fatty acids via fatty-acid synthase[1,2]. The structure determination of the holoenzymes of bacterial biotin-dependent carboxylases, which lack the characteristic CD, such as the pyruvate carboxylase (PC)[30], propionyl-CoA carboxylase23, 3-methyl-crotonyl-CoA carboxylase[24] and a long-chain acyl-CoA carboxylase[31] revealed strikingly divergent architectures despite a general conservation of all functional components In these structures, the BC and CT active sites are at distances between 40 and 80 Å, such that substrate transfer could be mediated solely by the mobility of the flexibly tethered BCCP. No effect of Ser1216 phosphorylation on ACC activity has been reported in higher eukaryotes
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