Structural insights into SETD3-mediated histidine methylation on β-actin
Structural insights into SETD3-mediated histidine methylation on β-actin
复制标题
SETD3 介导的 β-肌动蛋白组氨酸甲基化的结构见解。
DOI：
10.7554/elife.43676
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发表时间：
2019-02-20
期刊：
影响因子：
7.7
通讯作者：
Xu, Chao
中科院分区：
文献类型：
--
作者：
Guo, Qiong;Liao, Shanhui;Xu, Chao
SETD3是SET(SU(Var)3-9，ZEST的增强子，Trithorax)结构域蛋白超家族的成员，在缺氧性肺动脉高压、肌肉分化和肿瘤发生中起重要作用。此前，我们确定SETD3是肌动蛋白特异的甲基转移酶，它使His73的N3在β-肌动蛋白上甲基化(Kwiatkowski等人，2018年)。在这里，我们提出了两种结构的S-腺苷-L-同型半胱氨酸结合的SETD3与未经修饰的β-肌动蛋白多肽或其甲基化的变异体。在生化实验和酶活性分析的支持下，结构分析表明SETD3对β-肌动蛋白的识别和甲基化具有高度的序列特异性，并且SETD3和β-肌动蛋白在相互结合时都发生了显著的构象变化。综上所述，本研究首次揭示了SETD3介导的组氨酸甲基化对β-肌动蛋白的催化机制，这不仅揭示了蛋白质组氨酸甲基化现象，而且有助于设计SETD3的小分子抑制剂。
SETD3 is a member of the SET (Su(var)3-9, Enhancer of zeste, and Trithorax) domain protein superfamily and plays important roles in hypoxic pulmonary hypertension, muscle differentiation, and carcinogenesis. Previously, we identified SETD3 as the actin-specific methyl transferase that methylates the N3 of His73 on beta-actin (Kwiatkowski et al., 2018). Here, we present two structures of S-adenosyl-L-homocysteine-bound SETD3 in complex with either an unmodified beta-actin peptide or its His-methylated variant. Structural analyses, supported by biochemical experiments and enzyme activity assays, indicate that the recognition and methylation of beta-actin by SETD3 are highly sequence specific, and that both SETD3 and beta-actin adopt pronounced conformational changes upon binding to each other. In conclusion, this study is the first to show a catalytic mechanism of SETD3-mediated histidine methylation on beta-actin, which not only throws light on the protein histidine methylation phenomenon but also facilitates the design of small molecule inhibitors of SETD3.