Accessibility of Different Histone H3-Binding Domains of UHRF1 Is Allosterically Regulated by Phosphatidylinositol 5-Phosphate
Accessibility of Different Histone H3-Binding Domains of UHRF1 Is Allosterically Regulated by Phosphatidylinositol 5-Phosphate
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DOI：
10.1016/j.molcel.2014.04.004
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发表时间：
2014-06-19
期刊：
影响因子：
16
通讯作者：
Fischle, Wolfgang
中科院分区：
文献类型：
--
作者：
Gelato, Kathy A.;Tauber, Maria;Fischle, Wolfgang
UHRF1是一种多结构域蛋白，它将组蛋白H3修饰状态和DNA甲基化联系在一起。虽然其特定结构域的相互作用特性得到了很好的表征，但对这些功能的调节知之甚少。我们发现，UHRF1存在于不同的活性状态，结合未经修饰的H3或H3赖氨酸9三甲基化（H3K9me3）的修改。在C末端的一个多碱基区（PBR）通过占据一个必需的肽结合沟来阻断串联tudor结构域（TTD）与H3K9me3的相互作用。在这种状态下，植物同源结构域（PHD）介导与未修饰的H3尾的末端N端的相互作用。磷脂酰肌醇磷酸PI5 P与UHRF 1的PBR的结合导致结构域的构象重排，允许TTD结合H3K9me3。我们的研究结果定义了一个变构机制控制异染色质协会的一个重要的调控蛋白的表观遗传状态，并确定一个功能性的作用，神秘的核磷脂酰肌醇磷酸。
UHRF1 is a multidomain protein crucially linking histone H3 modification states and DNA methylation. While the interaction properties of its specific domains are well characterized, little is known about the regulation of these functionalities. We show that UHRF1 exists in distinct active states, binding either unmodified H3 or the H3 lysine 9 trimethylation (H3K9me3) modification. A polybasic region (PBR) in the C terminus blocks interaction of a tandem tudor domain (TTD) with H3K9me3 by occupying an essential peptide-binding groove. In this state the plant homeodomain (PHD) mediates interaction with the extreme N terminus of the unmodified H3 tail. Binding of the phosphatidylinositol phosphate PI5P to the PBR of UHRF1 results in a conformational rearrangement of the domains, allowing the TTD to bind H3K9me3. Our results define an allosteric mechanism controlling heterochromatin association of an essential regulatory protein of epigenetic states and identify a functional role for enigmatic nuclear phosphatidylinositol phosphates.