Crystal structure analysis of the PHD domain of the transcription co-activator pygopus
Crystal structure analysis of the PHD domain of the transcription co-activator pygopus
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DOI：
10.1016/j.jmb.2007.04.037
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发表时间：
2007-06-29
影响因子：
5.6
通讯作者：
Yokoyama, Shigeyuki
中科院分区：
文献类型：
--
作者：
Nakamura, Yoshihiro;Umehara, Takashi;Yokoyama, Shigeyuki
Wnt/β-catenin信号通路在动物发育和癌症中起着重要作用。Pygopus（Pygo）和Legless（Lgs）是最近发现的Wnt/β-cateniu转录机制复合物的核心组分，并且关键地参与调节Arm/β-catenin和T细胞因子（TCF）的转录。Lgs/Bcl 9作为Pygo和Arm/β-连环蛋白之间的衔接子发挥作用。在这里，我们报告的第一个晶体结构的植物同源结构域（PHD）手指的Pygopus（Pygol PHD），Pygo家族成员，这是必不可少的协会与LGS/Bcl 9。Pygol PHD结构形成了一个典型的PHD指状基序，由两个锌离子在交叉括号方案中协调稳定。令人惊讶的是，Pygol PHD结构域在晶体和溶液中都形成二聚体。这是已知的PHD结构域结构中二聚化的第一个结构证据。二聚体的形成是通过单体的胆固醇相关β 3链之间的反平行β-折叠的相互作用而发生的。Pygol PHD二聚体界面主要包含疏水残基。有趣的是，一些界面残基，如Met 372，Thr 373，Ala 376和Leu 380，据报道对于与Lgs/Bcl 9的关联是重要的，并且对于转录激活也是关键的。M372 A和L380 D突变体，以及几个周围的突变体，如S385 A和A386 D，表现出形成二聚体和与Lgs/Bcl 9的同源结构域1（HD 1）相互作用的能力降低。这些结果表明Pygol PHD二聚化对于Lgs/Bcl 9识别以及对于Wnt/β-连环蛋白信号传导途径的调节在功能上是重要的。(C)2007爱思唯尔有限公司保留所有权利。
The Wnt/beta-catenin signaling pathway plays important roles in animal development and cancer. Pygopus (Pygo) and Legless (Lgs) are recently discovered core components of the Wnt/beta-cateniu transcription machinery complex, and are crucially involved in the regulation of the transcription of the Arm/beta-catenin and T cell factors (TCF). Lgs/Bcl9 functions as an adaptor between Pygo and Arm/beta-catenin. Here, we report the first crystal structure of the plant homeodomain (PHD) finger of Pygopus (Pygol PHD), a Pygo family member, which is essential for the association with Lgs/Bcl9. The Pygol PHD structure forms a canonical PHD finger motif, stabilized by two Zn ions coordinated in a cross-brace scheme. Surprisingly, the Pygol PHD domain forms a dimer in both the crystals and solution. This is the first structural evidence for dimerization among the known PHD domain structures. The dimer formation occurs by the interactions of antiparallel beta-sheets between the symmetry-related beta 3 strands of the monomers. The Pygol PHD dimer interface mainly comprises hydrophobic residues. Interestingly, some of the interface residues, such as Met372, Thr373, Ala376 and Leu380, are reportedly important for the association with Lgs/Bcl9 and are also critical for transcriptional activation. The M372A and L380D mutants, and several surrounding mutants such as S385A and A386D, showed decreased ability to form dimers and to interact with the homology domain 1 (HD1) of Lgs/Bcl9. These results suggest that the Pygol PHD dimerization is functionally important for Lgs/Bcl9 recognition as well as for the regulation of the Wnt/beta-catenin signaling pathway. (C) 2007 Elsevier Ltd. All rights reserved.