Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1
Phosphorylation-mediated inactivation of coactivator-associated arginine methyltransferase 1
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DOI：
10.1073/pnas.0610792104
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发表时间：
2007-07-24
影响因子：
11.1
通讯作者：
Xu, Wei
中科院分区：
文献类型：
--
作者：
Higashimoto, Ken;Kuhn, Peter;Xu, Wei
多种蛋白质精氨酸甲基转移酶参与核受体的转录激活。辅激活子相关精氨酸甲基转移酶1（CARM 1）介导的组蛋白甲基化已被证明可以激活核受体依赖性转录;然而，对其酶活性的调节知之甚少。在这里，我们报告的甲基转移酶活性的CARM 1是负调控通过磷酸化在一个保守的丝氨酸残基。当丝氨酸残基突变为谷氨酸时，其模拟磷酸化的丝氨酸残基，突变体CARM 1表现出降低的结合甲基供体腺苷甲硫氨酸的能力和降低的组蛋白甲基化活性。此外，这种突变导致雌激素受体依赖性转录的CARM 1反式激活的抑制。我们的研究结果提供了一个例子，蛋白质精氨酸甲基转移酶活性的调节磷酸化。由于CARM 1是雌激素受体的一种有效的转录共激活因子，我们的研究结果表明，CARM 1的磷酸化是一种独特的机制，可使CARM 1调节的雌激素依赖性基因表达失活。
Multiple protein arginine methyltransferases are involved in transcriptional activation of nuclear receptors. Coactivator-associated arginine methyltransferase 1 (CARM1)-mediated histone methylation has been shown to activate nuclear receptor-dependent transcription; however, little is known about the regulation of its enzymatic activity. Here, we report that the methyltransferase activity of CARM1 is negatively regulated through phosphorylation at a conserved serine residue. When the serine residue is mutated to glutamic acid, which mimics the phosphorylated serine residue, the mutant CARM1 exhibits diminished ability to bind the methyl donor adenosylmethionine and diminished histone methylation activity. Moreover, such mutation leads to the inhibition of CARM1 transactivation of estrogen receptor-dependent transcription. Our results provide an example for the regulation of protein arginine methyltransferase activity by phosphorylation. As CARM1 is a potent transcriptional coactivator of estrogen receptor, our results suggest that phosphorylation of CARM1 serves as a unique mechanism for inactivating CARM1-regulated estrogen-dependent gene expression.