Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination
Regulation of coactivator complex assembly and function by protein arginine methylation and demethylimination
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DOI：
10.1073/pnas.0407159102
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发表时间：
2005-03-08
影响因子：
11.1
通讯作者：
Stallcup, MR
中科院分区：
文献类型：
--
作者：
Lee, YH;Coonrod, SA;Stallcup, MR
核受体通过将多个共激活子招募到特定靶基因的启动子来激活转录。 p160 共激活剂 [类固醇受体共激活剂-1、糖皮质激素受体相互作用蛋白 (GRIP1) 或甲状腺激素和视黄酸受体激活剂]、组蛋白乙酰转移酶 cAMP 反应元件结合蛋白结合蛋白 (CBP) 和 p300 以及组蛋白甲基转移酶共激活剂相关精氨酸的功能协同作用 甲基转移酶 (CARM1) 取决于 CARM1 的甲基转移酶活性。 CARM1 甲基化组蛋白 H3 和其他因子，包括 p300 的 N 末端区域。在这里，我们报告 CARM1 还会甲基化 p300 的 C 端 GRIP1 结合域 (GBD) 内的 Arg-2142。在 GBD 中，Arg-2088 和 Arg-2142 对于结合 GRIP1 都很重要。 Arg-2142 的甲基化在体外和体内抑制 GRIN 与 p300 的双分子相互作用。 p300 GBD 的甲基化标记可被肽基脱亚胺酶 4 去除，从而增强 p300-GRIP1 相互作用。这些甲基化和去甲基亚化事件还改变辅激活复合物的构象和活性并调节雌激素受体介导的转录，因此它们代表了调节辅激活复合物组装、构象和功能的独特机制。
Nuclear receptors activate transcription by recruiting multiple coactivators to the promoters of specific target genes. The functional synergy of the p160 coactivators [steroid receptor coactivator-1, glucocorticoid receptor interacting protein (GRIP1), or the activator for thyroid hormone and retinoid receptors], the histone acetyltransferases cAMP response element binding protein binding protein (CBP) and p300 and the histone methyltransferase coactivator-associated arginine methyltransferase (CARM1) depends on the methyltransferase activity of CARM1. CARM1 methylates histone H3 and other factors including the N-terminal region of p300. Here, we report that CARM1 also methylates Arg-2142 within the C-terminal GRIP1 binding domain (GBD) of p300. In the GBD, both Arg-2088 and Arg-2142 are important for binding GRIP1. Methylation of Arg-2142 inhibits the bimolecular interaction of GRIN to p300 in vitro and in vivo. This methylation mark of p300 GBD is removed by peptidyl deiminase 4, thereby enhancing the p300-GRIP1 interaction. These methylation and demethylimination events also alter the conformation and activity of the coactivator complex and regulate estrogen receptor-mediated transcription, and they thus represent unique mechanisms for regulating coactivator complex assembly, conformation, and function.