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

Cho YS,Lee JI,Shin D,Kim HT,Jung HY,Lee TG,Kang LW,Ahn YJ,Cho HS,Heo YS

doi

10.1016/j.bbrc.2009.11.029

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

187-92

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(09)02189-5

journal_volume

391

pub_type

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