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Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells.

Publication ,  Journal Article
Lu, G; Sun, H; She, P; Youn, J-Y; Warburton, S; Ping, P; Vondriska, TM; Cai, H; Lynch, CJ; Wang, Y
Published in: J Clin Invest
June 2009

The branched-chain amino acids (BCAA) are essential amino acids required for protein homeostasis, energy balance, and nutrient signaling. In individuals with deficiencies in BCAA, these amino acids can be preserved through inhibition of the branched-chain-alpha-ketoacid dehydrogenase (BCKD) complex, the rate-limiting step in their metabolism. BCKD is inhibited by phosphorylation of its E1alpha subunit at Ser293, which is catalyzed by BCKD kinase. During BCAA excess, phosphorylated Ser293 (pSer293) becomes dephosphorylated through the concerted inhibition of BCKD kinase and the activity of an unknown intramitochondrial phosphatase. Using unbiased, proteomic approaches, we have found that a mitochondrial-targeted phosphatase, PP2Cm, specifically binds the BCKD complex and induces dephosphorylation of Ser293 in the presence of BCKD substrates. Loss of PP2Cm completely abolished substrate-induced E1alpha dephosphorylation both in vitro and in vivo. PP2Cm-deficient mice exhibited BCAA catabolic defects and a metabolic phenotype similar to the intermittent or intermediate types of human maple syrup urine disease (MSUD), a hereditary disorder caused by defects in BCKD activity. These results indicate that PP2Cm is the endogenous BCKD phosphatase required for nutrient-mediated regulation of BCKD activity and suggest that defects in PP2Cm may be responsible for a subset of human MSUD.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

June 2009

Volume

119

Issue

6

Start / End Page

1678 / 1687

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Reactive Oxygen Species
  • Protein Subunits
  • Protein Binding
  • Phosphorylation
  • Phosphoprotein Phosphatases
  • Models, Animal
  • Mice, Knockout
  • Mice
  • Immunology
 

Citation

APA
Chicago
ICMJE
MLA
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Lu, G., Sun, H., She, P., Youn, J.-Y., Warburton, S., Ping, P., … Wang, Y. (2009). Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest, 119(6), 1678–1687. https://doi.org/10.1172/JCI38151
Lu, Gang, Haipeng Sun, Pengxiang She, Ji-Youn Youn, Sarah Warburton, Peipei Ping, Thomas M. Vondriska, Hua Cai, Christopher J. Lynch, and Yibin Wang. “Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells.J Clin Invest 119, no. 6 (June 2009): 1678–87. https://doi.org/10.1172/JCI38151.
Lu G, Sun H, She P, Youn J-Y, Warburton S, Ping P, et al. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009 Jun;119(6):1678–87.
Lu, Gang, et al. “Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells.J Clin Invest, vol. 119, no. 6, June 2009, pp. 1678–87. Pubmed, doi:10.1172/JCI38151.
Lu G, Sun H, She P, Youn J-Y, Warburton S, Ping P, Vondriska TM, Cai H, Lynch CJ, Wang Y. Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells. J Clin Invest. 2009 Jun;119(6):1678–1687.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

June 2009

Volume

119

Issue

6

Start / End Page

1678 / 1687

Location

United States

Related Subject Headings

  • Substrate Specificity
  • Reactive Oxygen Species
  • Protein Subunits
  • Protein Binding
  • Phosphorylation
  • Phosphoprotein Phosphatases
  • Models, Animal
  • Mice, Knockout
  • Mice
  • Immunology