Fiedler Marc, Sánchez-Barrena María José, Nekrasov Maxim, Mieszczanek Juliusz, Rybin Vladimir, Müller Jürg, Evans Phil, Bienz Mariann
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
Mol Cell. 2008 May 23;30(4):507-18. doi: 10.1016/j.molcel.2008.03.011.
Pygo and BCL9/Legless transduce the Wnt signal by promoting the transcriptional activity of beta-catenin/Armadillo in normal and malignant cells. We show that human and Drosophila Pygo PHD fingers associate with their cognate HD1 domains from BCL9/Legless to bind specifically to the histone H3 tail methylated at lysine 4 (H3K4me). The crystal structures of ternary complexes between PHD, HD1, and two different H3K4me peptides reveal a unique mode of histone tail recognition: efficient histone binding requires HD1 association, and the PHD-HD1 complex binds preferentially to H3K4me2 while displaying insensitivity to methylation of H3R2. Therefore, this is a prime example of histone tail binding by a PHD finger (of Pygo) being modulated by a cofactor (BCL9/Legless). Rescue experiments in Drosophila indicate that Wnt signaling outputs depend on histone decoding. The specificity of this process provided by the Pygo-BCL9/Legless complex suggests that this complex facilitates an early step in the transition from gene silence to Wnt-induced transcription.
Pygo和BCL9/Legless通过促进正常细胞和恶性细胞中β-连环蛋白/犰狳蛋白的转录活性来转导Wnt信号。我们发现，人类和果蝇的Pygo植物同源结构域（PHD）手指与BCL9/Legless的同源HD1结构域结合，从而特异性地结合赖氨酸4位点甲基化的组蛋白H3尾巴（H3K4me）。PHD、HD1与两种不同的H3K4me肽形成的三元复合物的晶体结构揭示了一种独特的组蛋白尾巴识别模式：有效的组蛋白结合需要HD1的结合，并且PHD-HD1复合物优先结合H3K4me2，而对H3R2的甲基化不敏感。因此，这是一个由辅助因子（BCL9/Legless）调节（Pygo的）PHD手指与组蛋白尾巴结合的典型例子。果蝇中的拯救实验表明，Wnt信号输出依赖于组蛋白解码。Pygo-BCL9/Legless复合物提供的这一过程的特异性表明，该复合物促进了从基因沉默到Wnt诱导转录转变的早期步骤。
