Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Acetyl-CoA carboxylases (ACCs) are critical enzymes regulating fatty acid metabolism.
• ACC activity is modulated by reversible phosphorylation, particularly by AMP-activated protein kinase (AMPK).
• ACCs are recognized as potential therapeutic targets for metabolic diseases like obesity and diabetes.

Purpose of the Study:

• To elucidate the structural basis of ACC2 inactivation by AMPK-mediated phosphorylation.
• To determine the mechanism by which the natural product soraphen A inhibits ACC activity.
• To provide insights into the regulation of fatty acid metabolism.

Main Methods:

• X-ray crystallography was employed to determine the structures of the biotin carboxylase (BC) domain of human ACC2.
• Structures were obtained for the phosphorylated form (pSer222) and in complex with soraphen A.
• Structural analysis focused on the dimer interface and ligand-binding sites.

Main Results:

• The crystal structure reveals that phosphorylated Ser222 in the BC domain of ACC2 binds to the dimer interface.
• This binding disrupts the polymerization necessary for ACC2 activity, explaining AMPK-mediated inactivation.
• The structure of ACC2 BC domain with soraphen A shows the compound occupies the pSer222 binding site, suggesting a shared inhibition mechanism.

Conclusions:

• AMPK inactivates ACC2 by phosphorylating Ser222, which disrupts enzyme dimerization and function.
• Soraphen A inhibits ACC2 through a mechanism analogous to AMPK phosphorylation, binding to the same site.
• These findings offer a molecular understanding of ACC regulation and potential drug development strategies for metabolic disorders.