Figure 1: Messenger RNA (mRNA; pink) bound to an RNA-binding protein (cyan). By altering the structure of mRNA, RNA-binding proteins such as the RNA helicase DDX3X can affect the expression of genes post transcription. © LAGUNA DESIGN/SCIENCE PHOTO LIBRARY
RIKEN researchers have discovered how an enzyme modifies gene expression by targeting certain stretches of messenger RNA (mRNA) while leaving others alone1. This finding could contribute to the rational design of drugs that tweak the enzyme's activity.
DNA is instantly recognizable from its double-stranded, helical structure. Similarly, mRNA, which is produced by transcribing sections of DNA, is not a linear ticker tape; rather it adopts various 3D structures, which influence how it is translated into proteins.
A special family of enzymes, known as RNA helicases, alters the structure of RNA. In particular, so-called DEAD-box RNA helicases straighten out RNA so that it becomes a single strand.
One member of DEAD-box RNA helicases, DDX3X, interacts only with certain sections of RNA, and in so doing influences how genes are expressed.
But how this specificity occurs on a molecular level was not known. This question is of more than simply academic importance.
"DDX3X is known to regulate the translation of mRNA into proteins, and malfunctions of DDX3X are closely associated with diseases such as cancer and neurological disorders," says Yuki Toyama of the RIKEN Center for Integrative Medical Sciences (IMS). "Therefore, investigating the molecular mechanisms underlying DDX3X function may pave the way for developing new therapeutic strategies."
Now, by using solution nuclear magnetic resonance (NMR) spectroscopy, Toyama and Ichio Shimada, also of IMS, along with Koh Takeuchi of the University of Tokyo, have determined the molecular mechanism of how DDX3X is selective in targeting certain sections of mRNA.
To the trio's surprise, an intrinsically disordered region of DDX3X turned out to be responsible for its selective recognition of mRNA.
"Since it lacks a well-defined structure, we never anticipated that the intrinsically disordered region of DDX3X would participate in the specific recognition of RNA structural motifs," says Shimada. "Typically, such precise molecular interactions are mediated through well-folded protein regions, often described by the 'lock-and-key' model."
The finding has implications for other proteins with intrinsically disordered regions and highlights the importance of NMR for analysing their structures.
"This finding highlights the importance of intrinsically disordered regions in fine-tuning cellular functions," says Toyama. "We believe that structural investigations of intrinsically disordered proteins, particularly using solution NMR, will become increasingly important."
The team is now exploring other aspects of the intrinsically disordered region of DDX3X, including how it defines localization on a subcellular scale. "This may reveal an additional layer of translation regulation by this protein," notes Shimada.
