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Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK |
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| Authors: | Yong Soon Cho Jae Il Lee Dongkyu Shin Hyun Tae Kim Tae Gyu Lee Yeh-Jin Ahn Yong-Seok Heo |
| Affiliation: | a R&D Center, CrystalGenomics, Inc., Seoul 138-739, Republic of Korea b Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea c Department of Chemistry, Konkuk University, Seoul 143-701, Republic of Korea d Department of Advanced Technology Fusion, Konkuk University, Seoul 143-701, Republic of Korea e Department of Life Science, College of Natural Sciences, Sangmyung University, Seoul 110-743, Republic of Korea |
| Abstract: | Acetyl-CoA carboxylases (ACCs) have been highlighted as therapeutic targets for obesity and diabetes, as they play crucial roles in fatty acid metabolism. ACC activity is regulated through the short-term mechanism of inactivation by reversible phosphorylation. Here, we report the crystal structures of the biotin carboxylase (BC) domain of human ACC2 phosphorylated by AMP-activated protein kinase (AMPK). The phosphorylated Ser222 binds to the putative dimer interface of BC, disrupting polymerization and providing the molecular mechanism of inactivation by AMPK. We also determined the structure of the human BC domain in complex with soraphen A, a macrocyclic polyketide natural product. This structure shows that the compound binds to the binding site of phosphorylated Ser222, implying that its inhibition mechanism is the same as that of phosphorylation by AMPK. |
| Keywords: | Acetyl-CoA carboxylase (ACC) Biotin carboxylase (BC) Fatty acid metabolism AMP-activated protein kinase (AMPK) Phosphorylation Short-term regulation Soraphen A Crystal structure |
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