Abstract
RNA-binding proteins play a key role in the regulation of all aspects of RNA metabolism, from the synthesis of RNA to its decay. Protein-RNA interactions have been thought to be mostly mediated by canonical RNA-binding domains that form stable secondary and tertiary structures. However, a number of pioneering studies over the past decades, together with recent proteome-wide data, have challenged this view, revealing surprising roles for intrinsically disordered protein regions in RNA binding. Here, we discuss how disordered protein regions can mediate protein-RNA interactions, conceptually grouping these regions into RS-rich, RG-rich, and other basic sequences, that can mediate both specific and non-specific interactions with RNA. Disordered regions can also influence RNA metabolism through protein aggregation and hydrogel formation. Importantly, protein-RNA interactions mediated by disordered regions can influence nearly all aspects of co- and post-transcriptional RNA processes and, consequently, their disruption can cause disease. Despite growing interest in disordered protein regions and their roles in RNA biology, their mechanisms of binding, regulation, and physiological consequences remain poorly understood. In the coming years, the study of these unorthodox interactions will yield important insights into RNA regulation in cellular homeostasis and disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12964-016-0132-3) contains supplementary material, which is available to authorized users.
Highlights
Structural requirements for RNA-protein interactions RNA-binding proteins (RBPs) assemble with RNA into dynamic ribonucleoprotein (RNP) complexes that mediate all aspects of RNA metabolism [1, 2]
RBPs interact with RNA was based on a limited number of globular RNA-binding domains (RBDs), which include RNA-recognition motif (RRM), K-homology domain (KH), double-stranded RBD, zinc fingers (Znf), DEAD box helicase domain, and others
Another study identified Fragile X mental retardation protein (FMRP) binding sites enriched in specific sequence motifs, where the KH2 domains emerged as the major specificity determinants [80]. These results suggest that the role of RGG-box in this RBP could be limited to increase the overall binding affinity of the protein, supporting the sequence-specific interactions mediated by the KH2 domains
Summary
Structural requirements for RNA-protein interactions RNA-binding proteins (RBPs) assemble with RNA into dynamic ribonucleoprotein (RNP) complexes that mediate all aspects of RNA metabolism [1, 2]. Alternative splicing at regions flanking the RGG-box alters FMRP’s capacity to bind RNA, to be methylated, and RG-rich repeats — The swiss-army knife of protein-RNA interactions A commonly occurring disordered RNA–binding motif in RBPs consists of repeats of arginine and glycine, termed RGG-boxes or GAR repeats.
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