The Fragile X Proteins Differentially Regulate Translation of Reporter mRNAs with G-quadruplex Structures.
The Fragile X Proteins Differentially Regulate Translation of Reporter mRNAs with G-quadruplex Structures.
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DOI：
10.1016/j.jmb.2021.167396
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发表时间：
2022-01-30
影响因子：
5.6
通讯作者：
Joseph S
中科院分区：
文献类型：
--
作者：
Edwards M;Joseph S
脆性X综合征，以及自闭症谱系障碍的一些表现，是由于脆性X智力低下蛋白（FMRP）缺乏引起的RNA调节不当所致。FMRP及其常染色体旁系同源物脆性X相关蛋白1和2（FXR1P/2P）涉及RNA调控的许多方面，从蛋白质合成到mRNA稳定性和衰变。关于脆性X相关蛋白（FXPs）在mRNA调控中的作用及其潜在的mRNA靶点的文献是大量的。因此，我们开发了一种方法，使用三个潜在的mRNA靶点来研究FXPs在翻译控制中的功能。简而言之，我们首先选择发现与FXPs相关并且其翻译受一种或多种FXPs影响的最佳mRNA候选物。然后，我们缩小了mRNA内的FXPs结合位点，分析了这种体外结合的强度，并确定了每种FXP如何影响具有结合位点的最小报告mRNA的翻译。总体而言，所有FXPs都以高亲和力结合含有G-四链体的RNA，如细胞周期蛋白依赖性激酶抑制剂p21和FMRP自身的编码区。有趣的是，FMRP明显地抑制每种mRNA的翻译，并且其方式似乎与其与每种mRNA的结合相关。相比之下，FXR 1 P/2 P抑制所有测试的mRNA。最后，尽管我们的RNA的结合是由于FXPs的含有RGG（甘氨酸-甘氨酸-甘氨酸）基序的C-末端区域，但该区域不足以引起翻译的抑制。
Fragile X Syndrome, as well as some manifestations of autism spectrum disorder, results from improper RNA regulation due to a deficiency of fragile X mental retardation protein (FMRP). FMRP and its autosomal paralogs, fragile X related proteins 1 & 2 (FXR1P/2P), have been implicated in many aspects of RNA regulation, from protein synthesis to mRNA stability and decay. The literature on the fragile X related proteins’ (FXPs) role in mRNA regulation and their potential mRNA targets is vast. Therefore, we developed an approach to investigate the function of FXPs in translational control using three potential mRNA targets. Briefly, we first selected top mRNA candidates found to be associated with the FXPs and whose translation are influenced by one or more of the FXPs. We then narrowed down the FXPs’ binding site(s) within the mRNA, analyzed the strength of this binding in vitro, and determined how each FXP affects the translation of a minimal reporter mRNA with the binding site. Overall, all FXPs bound with high affinity to RNAs containing G-quadruplexes, such as Cyclin Dependent Kinase Inhibitor p21 and FMRP’s own coding region. Interestingly, FMRP inhibited the translation of each mRNA distinctly and in a manner that appears to correlate with its binding to each mRNA. In contrast, FXR1P/2P inhibited all mRNAs tested. Finally, although binding of our RNAs was due to the RGG (arginine-glycine-glycine) motif-containing C-terminal region of the FXPs, this region was not sufficient to cause inhibition of translation.
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