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首页> 外文期刊>Nucleus >Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1
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Conserved linker regions and their regulation determine multiple chromatin-binding modes of UHRF1

机译：保守的接头区域及其调控决定了UHRF1的多种染色质结合模式

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Ubiquitin-like with PHD and RING Finger domains 1 (UHRF1) is an important nuclear protein that is mutated and aberrantly expressed in many tumors. The protein integrates different chromatin modifications and is essential for their maintenance throughout the cell cycle. Separate chromatin-binding modules of UHRF1 have been studied on a functional and structural level. The unmodified N-terminus of histone H3 is recognized by a PHD domain, while a TTD domain specifically interacts with histone H3 Lysine 9 trimethylation. A SRA region binds hemimethylatd DNA. Emerging evidence indicates that the modules of UHRF1 do not act independently of each other but establish complex modes of interaction with patterns of chromatin modifications. This multivalent readout is regulated by allosteric binding of phosphatidylinositol 5-phosphate to a region outside the PHD, TTD and SRA domains as well as by phosphorylation of one of the linker regions connecting these modules. Here, we summarize the current knowledge on UHRF1 chromatin interaction and introduce a novel model of conformational transitions of the protein that are directed by the flexible and highly charged linker regions. We propose that these are essential in setting up defined structural states of the protein where different domains or combinations thereof are available for binding chromatin modifications or are prevented from doing so. Lastly, we suggest that controlled tuning of intramolecular linker interactions by ligands and posttranslational modifications establishes a rational framework for comprehending UHRF1 regulation and putatively the working mode of other chromatin factors in different physiological contexts.
机译：具有PHD和RING指域1（UHRF1）的泛素样蛋白是一种重要的核蛋白，在许多肿瘤中均发生突变并异常表达。该蛋白整合了不同的染色质修饰，对于它们在整个细胞周期中的维持至关重要。已在功能和结构水平上研究了UHRF1的独立染色质结合模块。 PHD域可识别组蛋白H3的未修饰N末端，而TTD域则可与组蛋白H3赖氨酸9三甲基化发生特异性相互作用。 SRA区结合半甲基DNA。新兴证据表明，UHRF1的模块并非彼此独立起作用，而是与染色质修饰模式建立了复杂的相互作用模式。该多价读数受磷脂酰肌醇5-磷酸与PHD，TTD和SRA域外部的区域的变构结合以及连接这些模块的连接子区域之一的磷酸化所调节。在这里，我们总结了有关UHRF1染色质相互作用的当前知识，并介绍了由柔性和高电荷连接子区域控制的蛋白质构象转变的新模型。我们提出这些对于建立蛋白质的确定的结构状态至关重要，其中不同的结构域或其组合可用于结合染色质修饰，或阻止这样做。最后，我们建议通过配体和翻译后修饰对分子内接头相互作用的受控调节，为理解UHRF1调控建立了一个合理的框架，并推测了其他染色质因子在不同生理环境下的工作模式。

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