A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1
A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1
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DOI：
10.1042/bj20061900
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发表时间：
2007-06-01
影响因子：
4.1
通讯作者：
Wallberg, Annika E.
中科院分区：
文献类型：
--
作者：
Just Ribeiro, Mariana Saint;Hansson, Magnus L.;Wallberg, Annika E.
Notch 的配体激活导致 Notch IC（细胞内受体结构域）的释放，它易位到细胞核并与 DNA 结合蛋白 CSL 相互作用以控制特定靶基因的表达。除了配体介导的激活之外，Notch 信号传导还可以通过 Notch IC 与许多其他蛋白质的相互作用来进一步调节。先前已证明 MAML1 在 Notch IC 介导的转录中与组蛋白乙酰转移酶 p300 协同作用。在本研究中，我们表明 MAML1 的 N 端结构域直接与 p300 和组蛋白相互作用，并且 p300-MAML1 复合物特异性乙酰化染色质中的组蛋白 H3 和 H4 尾部。此外，p300 乙酰化 MAML1，MAML1 N 末端进化上保守的赖氨酸残基是 p300 介导的乙酰化的直接底物。 MAML1 的 N 端结构域包含一个脯氨酸重复基序 (PXPAAPAP)，先前已证明该基序存在于 p53 中，并且对于 p300-p53 相互作用很重要。我们发现 MAML1 脯氨酸重复基序与 p300 相互作用并增强体内 MAML1 N 末端的活性。这些发现表明，MAML1 的 N 末端结构域通过与 Notch、p300 和组蛋白直接相互作用，在 Notch 调节转录中发挥重要作用。
Ligand activation of Notch leads to the release of Notch IC (the intracellular receptor domain), which translocates to the nucleus and interacts with the DNA-binding protein CSL to control expression of specific target genes. In addition to ligand-mediated activation, Notch signalling can be further modulated by interactions of Notch IC with a number of other proteins. MAML1 has previously been shown to act co-operatively with the histone acetyltransferase p300 in Notch IC-mediated transcription. In the present study we show that the N-terminal domain of MAML1 directly interacts with both p300 and histones, and the p300-MAML1 complex specifically acetylates histone H3 and H4 tails in chromatin. Furthermore, p300 acetylates MAML1 and evolutionarily conserved lysine residues in the MAML1 N-terminus are direct substrates for p300-mediated acetylation. The N-terminal domain of MAML1 contains a proline repeat motif (PXPAAPAP) that was previously shown to be present in p53 and important for the p300-p53 interaction. We show that the MAML1 proline repeat motif interacts with p300 and enhances the activity of the MAML1 N-terminus in vivo. These findings suggest that the N-terminal domain of MAML1 plays an important role in Notch-regulated transcription, by direct interactions with Notch, p300 and histones.