Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK.
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.
Cho
Yong Soon
YS
R&D Center, CrystalGenomics, Inc., Seoul 138-739, Republic of Korea.
Lee
Jae Il
JI
Shin
Dongkyu
D
Kim
Hyun Tae
HT
Jung
Ha Yun
HY
Lee
Tae Gyu
TG
Kang
Lin-Woo
LW
Ahn
Yeh-Jin
YJ
Cho
Hyun-Soo
HS
Heo
Yong-Seok
YS
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
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