title: Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK.
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.
authors.affiliation: R&D Center, CrystalGenomics, Inc., Seoul 138-739, Republic of Korea.
authors.forename: Yong Soon
authors.initials: YS
authors.lastname: Cho
authors.forename: Jae Il
authors.initials: JI
authors.lastname: Lee
authors.forename: Dongkyu
authors.initials: D
authors.lastname: Shin
authors.forename: Hyun Tae
authors.initials: HT
authors.lastname: Kim
authors.forename: Ha Yun
authors.initials: HY
authors.lastname: Jung
authors.forename: Tae Gyu
authors.initials: TG
authors.lastname: Lee
authors.forename: Lin-Woo
authors.initials: LW
authors.lastname: Kang
authors.forename: Yeh-Jin
authors.initials: YJ
authors.lastname: Ahn
authors.forename: Hyun-Soo
authors.initials: HS
authors.lastname: Cho
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001710:Biotin / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D018942:Macrolides / Q000737:chemistry; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012694:Serine / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D018942:Macrolides; C086151:soraphen A; D012694:Serine; D001710:Biotin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C520105:ACACB protein, human; D000103:Acetyl-CoA Carboxylase