Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells
Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells
复制标题
DOI：
10.1172/jci38151
复制
发表时间：
2009-06-01
影响因子：
15.9
通讯作者：
Wang, Yibin
中科院分区：
文献类型：
--
作者：
Lu, Gang;Sun, Haipeng;Wang, Yibin
支链氨基酸（BCAA）是蛋白质稳态，能量平衡和营养信号所需的必需氨基酸。在BCAA缺乏的个体中，这些氨基酸可以通过抑制支链-α-酮酸脱氢酶（BCKD）复合物（其代谢中的限速步骤）来保留。BCKD通过其E1 α亚基在Ser 293处的磷酸化而被抑制，该磷酸化由BCKD激酶催化。在BCAA过量期间，磷酸化Ser 293（pSer 293）通过协同抑制BCKD激酶和未知线粒体内磷酸酶的活性而变得去磷酸化。使用公正的，蛋白质组学的方法，我们已经发现，一个细胞靶向磷酸酶，PP 2Cm，特异性结合的BCKD复合物，并诱导Ser 293在BCKD底物的存在下去磷酸化。PP 2Cm的损失完全废除底物诱导的Ela去磷酸化在体外和体内。PP 2Cm缺陷小鼠表现出BCAA分解代谢缺陷和类似于间歇性或中间型人类枫糖浆尿病（MSUD）的代谢表型，这是一种由BCKD活性缺陷引起的遗传性疾病。这些结果表明，PP 2Cm是营养介导的调节BCKD活性所需的内源性BCKD磷酸酶，并表明PP 2Cm的缺陷可能是人类MSUD的一个子集的原因。
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 E1 alpha 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 Ela 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.