The roles of structural dynamics in the cellular functions of RNAs

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Abstract

RNAs fold into 3D structures that range from simple helical elements to complex tertiary structures and quaternary ribonucleoprotein assemblies. The functions of many regulatory RNAs depend on how their 3D structure changes in response to a diverse array of cellular conditions. In this Review, we examine how the structural characterization of RNA as dynamic ensembles of conformations, which form with different probabilities and at different timescales, is improving our understanding of RNA function in cells. We discuss the mechanisms of gene regulation by microRNAs, riboswitches, ribozymes, post-transcriptional RNA modifications and RNA-binding proteins, and how the cellular environment and processes such as liquid-liquid phase separation may affect RNA folding and activity. The emerging RNA-ensemble–function paradigm is changing our perspective and understanding of RNA regulation, from in vitro to in vivo and from descriptive to predictive.

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Rethinking m6A Readers, Writers, and Erasers.

Kate Meyer, Samie R. Jaffrey (2017)

In recent years, m6A has emerged as an abundant and dynamically regulated modification throughout the transcriptome. Recent technological advances have enabled the transcriptome-wide identification of m6A residues, which in turn has provided important insights into the biology and regulation of this pervasive regulatory mark. Also central to our current understanding of m6A are the discovery and characterization of m6A readers, writers, and erasers. Over the last few years, studies into the function of these proteins have led to important discoveries about the regulation and function of m6A. However, during this time our understanding of these proteins has also evolved considerably, sometimes leading to the reversal of early concepts regarding the reading, writing and erasing of m6A. In this review, we summarize recent advances in m6A research, and we highlight how these new findings have reshaped our understanding of how m6A is regulated in the transcriptome.

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The energy landscapes and motions of proteins

Uli Frauenfelder, S G Sligar, P Wolynes (1991)

Recent experiments, advances in theory, and analogies to other complex systems such as glasses and spin glasses yield insight into protein dynamics. The basis of the understanding is the observation that the energy landscape is complex: Proteins can assume a large number of nearly isoenergetic conformations (conformational substates). The concepts that emerge from studies of the conformational substates and the motions between them permit a quantitative discussion of one simple reaction, the binding of small ligands such as carbon monoxide to myoglobin.

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Thiamine derivatives bind messenger RNAs directly to regulate bacterial gene expression.

Wade Winkler, Ali Nahvi, Ronald R. Breaker (2002)

Although proteins fulfil most of the requirements that biology has for structural and functional components such as enzymes and receptors, RNA can also serve in these capacities. For example, RNA has sufficient structural plasticity to form ribozyme and receptor elements that exhibit considerable enzymatic power and binding specificity. Moreover, these activities can be combined to create allosteric ribozymes that are modulated by effector molecules. It has also been proposed that certain messenger RNAs might use allosteric mechanisms to mediate regulatory responses depending on specific metabolites. We report here that mRNAs encoding enzymes involved in thiamine (vitamin B(1)) biosynthesis in Escherichia coli can bind thiamine or its pyrophosphate derivative without the need for protein cofactors. The mRNA-effector complex adopts a distinct structure that sequesters the ribosome-binding site and leads to a reduction in gene expression. This metabolite-sensing regulatory system provides an example of a 'riboswitch' whose evolutionary origin might pre-date the emergence of proteins.