Structural insight into histone recognition by the ING PHD fingers.
Structural insight into histone recognition by the ING PHD fingers.
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DOI：
10.2174/138945009788185040
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发表时间：
2009-05
影响因子：
3.2
通讯作者：
Kutateladze TG
中科院分区：
文献类型：
--
作者：
Champagne KS;Kutateladze TG
生长抑制剂（ING）肿瘤抑制因子与肿瘤发生、DNA损伤修复控制、细胞衰老和凋亡有关。ING家族的所有成员都含有独特的氨基末端区域和羧基末端植物同源结构域（PHD）指。虽然氨基末端结构域与许多蛋白质效应物相关，包括组蛋白去乙酰化酶（HDAC）和组蛋白乙酰转移酶（HAT）复合物的不同组分，但PHD手指与赖氨酸4三甲基化的组蛋白H3 （H3K4me3）结合强烈且特异性。在本文中，我们描述了ING1-5 PHD手指识别H3K4me3的分子机制，分析了组蛋白特异性的决定因素，并比较了PHD手指亚群中的生物活性和结构。ING PHD手指与H3K4me3肽复合物的原子分辨率结构表明，组蛋白尾部结合在一个大而深的结合位点上，覆盖了蛋白质表面的近三分之一。广泛的分子间氢键网络、疏水和阳离子-π接触以及互补的表面相互作用协调了H3K4me3肽的前六个残基。三甲基化的Lys4占据一个细长的凹槽，由PHD指的高度保守的芳香和疏水残基形成，而邻近的凹槽容纳Arg2。这两个凹槽由一个狭窄的通道连接，其小尺寸决定了PHD手指的特异性，排除了与其他修饰组蛋白肽的相互作用。ING PHD指与H3K4me3的结合在调节染色质乙酰化中起关键作用。ING蛋白的功能是将HDAC和HAT酶复合物物理地连接到染色质上。在这篇综述中，我们还强调了最近在了解ING肿瘤抑制因子的生物学和致瘤活性的分子基础方面取得的进展。
The Inhibitor of Growth (ING) tumor suppressors are implicated in oncogenesis, control of DNA damage repair, cellular senescence and apoptosis. All members of the ING family contain unique amino-terminal regions and a carboxy-terminal plant homeodomain (PHD) finger. While the amino-terminal domains associate with a number of protein effectors including distinct components of histone deacetylase (HDAC) and histone acetyltransferase (HAT) complexes, the PHD finger binds strongly and specifically to histone H3 trimethylated at lysine 4 (H3K4me3). In this review we describe the molecular mechanism of H3K4me3 recognition by the ING1-5 PHD fingers, analyze the determinants of the histone specificity and compare the biological activities and structures within subsets of PHD fingers. The atomic-resolution structures of the ING PHD fingers in complex with a H3K4me3 peptide reveal that the histone tail is bound in a large and deep binding site encompassing nearly one-third of the protein surface. An extensive network of intermolecular hydrogen bonds, hydrophobic and cation-π contacts, and complementary surface interactions coordinate the first six residues of the H3K4me3 peptide. The trimethylated Lys4 occupies an elongated groove, formed by the highly conserved aromatic and hydrophobic residues of the PHD finger, whereas the adjacent groove accommodates Arg2. The two grooves are connected by a narrow channel, the small size of which defines the PHD finger’s specificity, excluding interactions with other modified histone peptides. Binding of the ING PHD fingers to H3K4me3 plays a critical role in regulating chromatin acetylation. The ING proteins function as tethering molecules that physically link the HDAC and HAT enzymatic complexes to chromatin. In this review we also highlight progress recently made in understanding the molecular basis underlying biological and tumorigenic activities of the ING tumor suppressors.
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影响因子：
2.9
作者：
Champagne KS;Saksouk N;Peña PV;Johnson K;Ullah M;Yang XJ;Côté J;Kutateladze TG
通讯作者：
Kutateladze TG
影响因子：
56.9
作者：
Huang, Y;Fang, J;Xu, RM
通讯作者：
Xu, RM
影响因子：
64.5
作者：
Gozani, O;Karuman, P;Yuan, JY
通讯作者：
Yuan, JY
影响因子：
64.5
作者：
Iwase, Shigeki;Lan, Fei;Shi, Yang
通讯作者：
Shi, Yang
影响因子：
16
作者：
Fiedler, Marc;Sanchez-Barrena, Maria Jose;Nekrasov, Maxim;Mieszczanek, Juliusz;Rybin, Vladimir;Mueller, Juerg;Evans, Phil;Bienz, Mariann
通讯作者：
Bienz, Mariann