Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily.
Effects of carboxyl-terminal methylation on holoenzyme function of the PP2A subfamily.
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DOI：
10.1042/bst20200177
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发表时间：
2020-10-30
影响因子：
3.9
通讯作者：
Kettenbach AN
中科院分区：
文献类型：
--
作者：
Nasa I;Kettenbach AN
磷酸蛋白磷酸酶（PPPs）是酵母和人类中高度保守的酶，催化细胞中大部分丝氨酸和苏氨酸的去磷酸化。为了实现底物特异性和选择性，PPP形成由催化、结构/支架和调节亚基组成的多聚体全酶。对于PPPs的蛋白磷酸酶2A（PP 2A）亚家族，全酶组装至少部分地由不寻常的羧基末端甲基化（通常称为“甲基化”）调节。羧基末端甲基化由亮氨酸羧基甲基转移酶-1（LCMT 1）催化，LCMT 1利用S-腺苷甲硫氨酸（SAM）作为甲基供体，并由蛋白磷酸酶甲基酯酶1（PME 1）去除。对于PP 2A，甲基化决定了调节亚基的选择，从而决定了下游磷酸化信号传导。有趣的是，PP 2A调节亚基有四个家族，每个家族都表现出不同水平的甲基化敏感性。因此，PP 2A甲基化化学计量的变化改变了细胞中PP 2A全酶的补体，并产生了不同的激酶对抗模式。重要的是，在几种疾病中观察到通过甲基化失调的PP 2A信号传导的选择性失活，最突出的是阿尔茨海默病（AD）。在这篇综述中，我们专注于PP 2A亚家族（PP 2A，PP 4和PP 6）的羧基末端甲基化如何调节全酶功能，从而磷酸化信号，重点是AD。
Phosphoprotein Phosphatases (PPPs) are enzymes highly conserved from yeast and human and catalyze the majority of serine and threonine dephosphorylation in cells. To achieve substrate specificity and selectivity, PPPs form multimeric holoenzymes consisting of catalytic, structural/scaffolding, and regulatory subunits. For the Protein Phosphatase 2A (PP2A)-subfamily of PPPs, the holoenzyme assembly is at least in part regulated by an unusual carboxyl-terminal methyl-esterification, commonly referred to as “methylation”. Carboxyl-terminal methylation is catalyzed by leucine carboxyl methyltransferase-1 (LCMT1) that utilizes S-adenosyl-methionine (SAM) as the methyl donor and removed by protein phosphatase methylesterase 1 (PME1). For PP2A, methylation dictates regulatory subunit selection and thereby downstream phosphorylation signaling. Intriguingly, there are four families of PP2A regulatory subunits, each exhibiting different levels of methylation sensitivity. Thus, changes in PP2A methylation stoichiometry alters the complement of PP2A holoenzymes in cells and creates distinct modes of kinase opposition. Importantly, selective inactivation of PP2A signaling through the deregulation of methylation is observed in several diseases, most prominently Alzheimer’s disease (AD). In this review, we focus on how methylation of the carboxyl-terminus of the PP2A subfamily (PP2A, PP4, and PP6) regulates holoenzyme function and thereby phosphorylation signaling, with an emphasis on AD.
影响因子：
3.7
作者：
MacKay KB;Tu Y;Young SG;Clarke SG
通讯作者：
Clarke SG