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

Yong Soon Cho, Jae Il Lee, Dongkyu Shin, Hyun Tae Kim, Ha Yun Jung, Tae Gyu Lee, Lin Woo Kang, Yeh Jin Ahn, Hyun Soo Cho, Yong Seok Heo

Research output: Contribution to journalArticle

40 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)187-192
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume391
Issue number1
DOIs
Publication statusPublished - 2010 Jan 1

Fingerprint

biotin carboxylase
Phosphorylation
AMP-Activated Protein Kinases
Acetyl-CoA Carboxylase
Polyketides
Medical problems
Biological Products
Metabolism
Polymerization
Dimers
Fatty Acids
Obesity
Crystal structure
Binding Sites

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cho, Yong Soon ; Lee, Jae Il ; Shin, Dongkyu ; Kim, Hyun Tae ; Jung, Ha Yun ; Lee, Tae Gyu ; Kang, Lin Woo ; Ahn, Yeh Jin ; Cho, Hyun Soo ; Heo, Yong Seok. / Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. In: Biochemical and Biophysical Research Communications. 2010 ; Vol. 391, No. 1. pp. 187-192.
@article{d69db2df6b214a66b85e0d97acde23ef,
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.",
author = "Cho, {Yong Soon} and Lee, {Jae Il} and Dongkyu Shin and Kim, {Hyun Tae} and Jung, {Ha Yun} and Lee, {Tae Gyu} and Kang, {Lin Woo} and Ahn, {Yeh Jin} and Cho, {Hyun Soo} and Heo, {Yong Seok}",
year = "2010",
month = "1",
day = "1",
doi = "10.1016/j.bbrc.2009.11.029",
language = "English",
volume = "391",
pages = "187--192",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "1",

}

Cho, YS, Lee, JI, Shin, D, Kim, HT, Jung, HY, Lee, TG, Kang, LW, Ahn, YJ, Cho, HS & Heo, YS 2010, 'Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK', Biochemical and Biophysical Research Communications, vol. 391, no. 1, pp. 187-192. https://doi.org/10.1016/j.bbrc.2009.11.029

Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK. / Cho, Yong Soon; Lee, Jae Il; Shin, Dongkyu; Kim, Hyun Tae; Jung, Ha Yun; Lee, Tae Gyu; Kang, Lin Woo; Ahn, Yeh Jin; Cho, Hyun Soo; Heo, Yong Seok.

In: Biochemical and Biophysical Research Communications, Vol. 391, No. 1, 01.01.2010, p. 187-192.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK

AU - Cho, Yong Soon

AU - Lee, Jae Il

AU - Shin, Dongkyu

AU - Kim, Hyun Tae

AU - Jung, Ha Yun

AU - Lee, Tae Gyu

AU - Kang, Lin Woo

AU - Ahn, Yeh Jin

AU - Cho, Hyun Soo

AU - Heo, Yong Seok

PY - 2010/1/1

Y1 - 2010/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=72949114063&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=72949114063&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2009.11.029

DO - 10.1016/j.bbrc.2009.11.029

M3 - Article

C2 - 19900410

AN - SCOPUS:72949114063

VL - 391

SP - 187

EP - 192

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 1

ER -