Abstract
Complex RNA–RNA interactions are increasingly known to play key roles in numerous biological processes from gene expression control to ribonucleoprotein granule formation. By contrast, the nature of these interactions and characteristics of their interfaces, especially those that involve partially or wholly structured RNAs, remain elusive. Herein, we discuss different modalities of RNA–RNA interactions with an emphasis on those that depend on secondary, tertiary, or quaternary structure. We dissect recently structurally elucidated RNA–RNA complexes including RNA triplexes, riboswitches, ribozymes, and reverse transcription complexes. These analyses highlight a reciprocal relationship that intimately links RNA structure formation with RNA–RNA interactions. The interactions not only shape and sculpt RNA structures but also are enabled and modulated by the structures they create. Understanding this two-way relationship between RNA structure and interactions provides mechanistic insights into the expanding repertoire of noncoding RNA functions, and may inform the design of novel therapeutics that target RNA structures or interactions.
Highlights
Biomolecules have evolved to function in coordination with each other in crowded intracellular environments in which new molecular interfaces and connections develop continuously
We examine three primary classes of RNA–RNA interactions—those between single-stranded RNAs, between ssRNA and structured RNAs, and between structured RNAs
Base intercalation is a key interaction that mediates the formation of the canonical tRNA elbow structure, where the G18 residue of D-loop inserts into the stacking gap of the T-loop [9,10,11], as well as the interdigitated double T-loop motif (IDTM) found in most T-box riboswitches and RNases P, which is formed by the reciprocal intercalation of two T-loops in head-to-tail opposition [12,13]
Summary
Biomolecules have evolved to function in coordination with each other in crowded intracellular environments in which new molecular interfaces and connections develop continuously. In the primordial RNA world, RNA–RNA and RNA–metabolite interactions were responsible for executing and regulating most if not all aspects of the metabolism. Not all of these RNA interfaces have been lost. Using specific examples from triplexes to ribozymes, with particular emphasis on those with high-resolution structural information, we derive general trends and themes that are common to these diverse systems These insights could help understand other RNA–RNA interaction systems whose structures remain unknown, and further inform the design of strategies or therapeutics that modulate RNA–RNA interactions important for cellular physiology or pathology
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