Toyama Yuki, Takeuchi Koh, Shimada Ichio
RIKEN Center for Biosystems Dynamics Research (BDR), Yokohama, Kanagawa, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.
Nat Commun. 2025 Aug 28;16(1):7762. doi: 10.1038/s41467-025-62806-7.
DDX3X, a member of the DEAD-box RNA helicase family, plays a central role in the translational regulation of gene expression through its unwinding activity toward complex RNA structures in messenger RNAs (mRNAs). Although DDX3X is known to selectively stimulate the translation of a subset of genes, a specific sequence motif has not been identified; thus, the molecular mechanism underlying this selectivity remains elusive. Using solution nuclear magnetic resonance (NMR) spectroscopy, we demonstrate that the N-terminal intrinsically disordered region (IDR) of DDX3X plays a critical role in the binding and unwinding of structured RNAs. We propose that the selectivity toward target transcripts is mediated by its preferential binding to structured motifs, particularly the G-quadruplex structure, through arginine-rich segments within the N-terminal IDR. Our results provide a molecular basis for understanding translational regulation by DDX3X and highlight the remarkable role of the flexible IDR in controlling the cellular translational landscape.
DDX3X是DEAD-box RNA解旋酶家族的成员，通过其对信使核糖核酸（mRNA）中复杂RNA结构的解旋活性，在基因表达的翻译调控中发挥核心作用。尽管已知DDX3X能选择性地刺激一部分基因的翻译，但尚未鉴定出特定的序列基序；因此，这种选择性背后的分子机制仍然难以捉摸。利用溶液核磁共振（NMR）光谱，我们证明了DDX3X的N端内在无序区域（IDR）在结构化RNA的结合和解旋中起关键作用。我们提出，对靶转录本的选择性是由其通过N端IDR内富含精氨酸的片段与结构化基序，特别是G-四链体结构的优先结合介导的。我们的结果为理解DDX3X的翻译调控提供了分子基础，并突出了灵活的IDR在控制细胞翻译格局中的显著作用。
