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J Biol Chem. 2012 Jul 6;287(28):23397-406. doi: 10.1074/jbc.M112.351031. Epub 2012 May 15.

Tissue-specific and nutrient regulation of the branched-chain α-keto acid dehydrogenase phosphatase, protein phosphatase 2Cm (PP2Cm).

Author information

1
Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.

Abstract

Branched-chain amino acid (BCAA) homeostasis is maintained through highly regulated catabolic activities where the rate-limiting step is catalyzed by branched-chain α-keto dehydrogenase (BCKD). Our previous study has identified a mitochondria-targeted protein phosphatase, PP2Cm, as the BCKD phosphatase and thus serves as a key regulator for BCAA catabolism. In this report, we performed comprehensive molecular and biochemical studies of PP2Cm regulation using both in vivo and in vitro systems. We show that PP2Cm expression is highly enriched in brain, heart, liver, kidney, and diaphragm, but low in skeletal muscle. The PP2Cm expression is regulated at the transcriptional level in response to nutrient status. Furthermore, we have established that PP2Cm interacts with the BCKD E2 subunit and competes with the BCKD kinase in a substrate-dependent and mutually exclusive manner. These data suggest that BCAA homeostasis is at least in part contributed by nutrient-dependent PP2Cm expression and interaction with the BCKD complex. Finally, a number of human PP2Cm single nucleotide polymorphic changes as identified in the public data base can produce either inactive or constitutive active mutant phosphatases, suggesting that putative PP2Cm mutations may contribute to BCAA catabolic defects in human.

PMID:
22589535
PMCID:
PMC3390616
DOI:
10.1074/jbc.M112.351031
[Indexed for MEDLINE]
Free PMC Article

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