The Structure of the ZMYND8/Drebrin Complex Suggests a Cytoplasmic Sequestering Mechanism of ZMYND8 by Drebrin
The Structure of the ZMYND8/Drebrin Complex Suggests a Cytoplasmic Sequestering Mechanism of ZMYND8 by Drebrin
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ZMYND8/Drebrin 复合物的结构表明 Drebrin 对 ZMYND8 的细胞质隔离机制
DOI：
10.1016/j.str.2017.08.014
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发表时间：
2017
期刊：
影响因子：
5.7
通讯作者：
Zhang Mingjie
中科院分区：
文献类型：
--
作者：
Yao Ningning;Li Jianchao;Liu Haiyang;Wan Jun;Liu Wei;Zhang Mingjie
肌动蛋白结合蛋白Dreplastin的功能障碍与多种人类疾病有关，如阿尔茨海默病、认知障碍、癌症和消化系统疾病，尽管其机制知之甚少。Dreplasty的ADF-H结构域不含肌动蛋白结合和解聚活性。相反，它与组蛋白标记阅读器ZMYND 8结合。在这里，我们提出了高分辨率的晶体结构的Dreplasty ADF-H与ZMYND 8 PHD-BROMO-PWWP串联复合，阐明了机制的基础上，管理高度特异性的相互作用的两种蛋白质。该结构揭示了ZMYND 8 PHD-BROMO-PWWP串联体形成了结合Dreplastin ADF-H所必需的结构超模块。Dreglycoprotein ADF-H与修饰的组蛋白竞争结合ZMYND 8。在活细胞中，结合Drelycidin可以将ZMYND 8从细胞核穿梭至细胞质。综上所述，我们的研究揭示了ADF-H结构域的非肌动蛋白靶向结合模式，并表明Dredrone可能通过其细胞质螯合调节表观遗传阅读器ZMYND 8的活性。
Malfunctions of the actin binding protein Drebrin have been implicated in various human diseases such as Alzheimer's disease, cognitive impairments, cancer, and digestive disorders, though with poorly understood mechanisms. The ADF-H domain of Drebrin does not contain actin binding and depolymerizing activity. Instead, it binds to a histone marker reader, ZMYND8. Here we present the high-resolution crystal structure of Drebrin ADF-H in complex with the ZMYND8 PHD-BROMO-PWWP tandem, elucidating the mechanistic basis governing the highly specific interaction of the two proteins. The structure reveals that the ZMYND8 PHD-BROMO-PWWP tandem forms a structural supramodule that is necessary for binding to Drebrin ADF-H. Drebrin ADF-H competes with modified histone for binding to ZMYND8. Binding of Drebrin can shuttle ZMYND8 from nucleus to cytoplasm in living cells. Taken together, our study uncovers a non-actin target binding mode for ADF-H domains, and suggests that Drebrin may regulate activities of epigenetic reader ZMYND8 via its cytoplasmic sequestration.