RNA, or ribonucleic acid, is a pivotal molecule in the realm of biology, playing a crucial role in gene expression and various cellular functions. Understanding the intricate mechanisms governing RNA folding is essential for comprehending its functions.

In this article, we delve into the latest developments in the study of RNA folding, spanning from in vitro experiments to in vivo investigations.

What is RNA?

RNA, a polymeric molecule, is indispensable for numerous biological processes, including genetic coding, decoding, gene control, and expression. It is one of the four primary macromolecules fundamental to all life forms, alongside lipids, proteins, and carbohydrates. RNA's roles within cells vary, encompassing functions such as transcriptional control, translation, temperature sensing, and RNA turnover.

Can RNA Fold Itself?

RNA folding is a fundamental mechanism underlying its functionality. While substantial progress has been made in understanding RNA folding in vitro, the principles governing intracellular RNA structure development are still in their infancy. RNA molecules must adopt specific three-dimensional structures to perform their functions, transitioning from a disordered state to a functional conformation—a process known as folding. Research on in vitro RNA folding has predominantly employed catalytic RNAs as model systems.

RNA's Folding Challenges

RNA encounters two primary folding challenges: the propensity for misfolding and the need for specific RNA-binding proteins or high salt concentrations to stabilize the tertiary structure. Intermediate folding states along the path to the functional structure play a vital role in RNA folding. Categorizing these intermediate states has been a focus of extensive research, even at the atomic level.

Exploring In Vivo RNA Folding Pathways

While in vitro studies have provided valuable insights, understanding RNA folding in vivo is equally crucial, given the differences in cellular environments. The P4-P6 and P3-P9 structural domains of Group I introns, specifically the Tetrahymena ribozyme, have been meticulously studied during in vitro folding. In vivo observations using DMS chemical probing in E. coli revealed that intron mutations can affect the tertiary structure differently, shedding light on the hierarchical folding process.

Current Techniques for Investigating RNA Structure in Vivo

Studying RNA structure and function within living cells presents unique challenges. Various experimental techniques, including chemical methods, have been employed. Dimethyl sulfate (DMS), lead-(II)-acetate, and hydroxyl radical footprinting are effective tools for probing RNA structures and interactions in vivo. UV-crosslinking and chemogenetic methods like NAIM offer insights into RNA-protein interactions at an atomic level.

Conclusion

Despite significant progress in understanding RNA folding, there is much more to explore in the realm of intracellular RNA structures. Novel methods, including those utilizing NMR for analyzing folding kinetics in vivo, are crucial for advancing our knowledge of the mechanisms driving RNA folding within living cells. Unlocking these secrets will continue to unveil the mysteries of cellular processes and gene expression.

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