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

doi:10.1016/j.bbrc.2009.11.029

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 journal › Article › peer-review

61 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 language	English
Pages (from-to)	187-192
Number of pages	6
Journal	Biochemical and Biophysical Research Communications
Volume	391
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2009.11.029
Publication status	Published - 2010 Jan 1

Bibliographical note

Funding Information:
We thank the staffs at beamline 4A, Pohang Light Source (PLS), for their assistance. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD). (KRF-2007-313- C00621 ) and by a Grant (Code # 20070501034003) from BioGreen 21 Program, Rural Development Administration, South Korea. And this work was supported by the Korea Research Foundation grants funded by the Korean Government (KRF-2008-313-C00745and KRF-2006-005- J04502 to H.S.C).

All Science Journal Classification (ASJC) codes

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2009.11.029

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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}",

note = "Funding Information: We thank the staffs at beamline 4A, Pohang Light Source (PLS), for their assistance. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD). (KRF-2007-313- C00621 ) and by a Grant (Code # 20070501034003) from BioGreen 21 Program, Rural Development Administration, South Korea. And this work was supported by the Korea Research Foundation grants funded by the Korean Government (KRF-2008-313-C00745and KRF-2006-005- J04502 to H.S.C).",

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doi = "10.1016/j.bbrc.2009.11.029",

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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

N1 - Funding Information: We thank the staffs at beamline 4A, Pohang Light Source (PLS), for their assistance. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD). (KRF-2007-313- C00621 ) and by a Grant (Code # 20070501034003) from BioGreen 21 Program, Rural Development Administration, South Korea. And this work was supported by the Korea Research Foundation grants funded by the Korean Government (KRF-2008-313-C00745and KRF-2006-005- J04502 to H.S.C).

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.

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

Abstract

Bibliographical note

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