RNA-protein interactions: disorder, moonlighting and junk contribute to eukaryotic complexity

Abstract

RNA-protein interactions are crucial for most biological processes in all organisms. However, it appears that the complexity of RNA-based regulation increases with the complexity of the organism, creating additional regulatory circuits, the scope of which is only now being revealed. It is becoming apparent that previously unappreciated features, such as disordered structural regions in proteins or non-coding regions in DNA leading to higher plasticity and pliability in RNA-protein complexes, are in fact essential for complex, precise and fine-tuned regulation. This review addresses the issue of the role of RNA-protein interactions in generating eukaryotic complexity, focusing on the newly characterized disordered RNA-binding motifs, moonlighting of metabolic enzymes, RNA-binding proteins interactions with different RNA species and their participation in regulatory networks of higher order.

Keywords: RNA-binding proteins; eukaryotic complexity; intrinsically disordered proteins; non-coding RNA; protein moonlighting.

Figure 1.

RNA–protein functional units in the cell rely on disordered RBPs. Most of the RNA is in the nucleus, where it is transcribed, spliced, exported and/or degraded, stored or engaged in chromatin regulation (lncRNA). Mature RNA, which is exported to the cytoplasm, can either be translated on the ribosome or also degraded, stored or transported to the site of localized translation (mostly in neurons or developing embryo). Different forms of cellular stress stall translation and freeze RNA–protein translation complexes in stress granules, until optimal conditions are restored or the cell dies. Cellular RNA can be bound in big macromolecular complexes (spliceosome or ribosome) or be stored, sequestered, transported or degraded in different types of RNA granules. In both cases, proteins forming these ribonucleic entities are significantly disordered and the disorder is crucial for their existence. EJC, exon-junction complex.

Figure 2.

The number of lncRNA is much higher in more complex eukaryotes, while the number of RBPs remains similar. Bubble plot showing the proportion of protein coding to lncRNA coding genes across species. The number of lncRNA coding genes from the NONCODEV5 database [65]. The bubble size denotes the number of RBPs [2]. Number of datasets: yeast (Saccharomyces cerevisiae)—8, human (Homo sapiens)—6, mouse (Mus musculus)—6, Arabidopsis thaliana—3, fruit fly (Drosophila melanogaster)—2, Caenorhabditis elegans—1.

Figure 3.

RNA occupies a central position in cellular regulatory circuits. Transcription of RNA, its quality, stability and translation are regulated by proteins. However, the central dogma in which DNA encodes proteins via RNA needs to be updated, taking into account the role of RNA as a main player in the regulation of expression, not only as a messenger. Almost all DNA is transcribed, but only 1–2% encodes proteins. At the same time, the estimates of the ENCODE consortium [105] assign biochemical function to 80% of the genome. Thus, the activity of the non-coding part of the genome encompasses the regulation of the RNA itself (microRNA, lncRNA and the other types of ncRNA), regulation of DNA (chromatin architecture, transcription, epigenetic modifications) and direct regulation of protein activity. As stressed in the article, eukaryotic RBPs have multiple functions.