Abstract
RNA-binding proteins (RBPs) have intrinsically disordered regions (IDRs) whose biophysical properties have yet to be explored to the same extent as those of the folded RNA interacting domains. These IDRs are essential to the formation of biomolecular condensates, such as stress and RNA granules, but dysregulated assembly can be pathological. Because of their structural heterogeneity, IDRs are best studied by NMR spectroscopy. In this study, we used NMR spectroscopy to investigate the structural propensity and self-association of the IDR of the RBP Musashi-1. We identified two transient α-helical regions (residues ~208–218 and ~270–284 in the IDR, the latter with a polyalanine tract). Strong NMR line broadening in these regions and circular dichroism and micrography data suggest that the two α-helical elements and the hydrophobic residues in between may contribute to the formation of oligomers found in stress granules and implicated in Alzheimer’s disease. Bioinformatics analysis suggests that polyalanine stretches in the IDRs of RBPs may have evolved to promote RBP assembly.
Highlights
The human genome encodes more than 1500 RNA-binding proteins (RBPs) [1]
Pioneering studies have shown that some RBPs use their intrinsically disordered regions (IDRs) to form “dynamic fibers” that may play a role in organizing membraneless cellular structures, such as RNA granules and stress granules [8]
Another function mediated by IDRs is liquid–liquid phase separation (LLPS), which has recently been shown to govern the coordination of cellular membraneless organelles [9,10]
Summary
The human genome encodes more than 1500 RNA-binding proteins (RBPs) [1]. In addition to canonical RNA-binding domains, most, if not all, RBPs have intrinsically disordered regions (IDRs) [2,3,4,5], whose importance has only recently come to light [6,7]. Another unusual feature of its primary sequence is the presence of a polyalanine tract (eight consecutive alanines) in the center, and contrary to the IDRs of many other RBPs [4,5], there are no SR-repeats, RG/RGG motifs, Q/N-rich stretches, or [G/S]Y[G/S] motifs (Figure 1H) How this unique sequence is involved in neurodegenerative disease and/or stress granule recruitment are questions that remain to be answered. Even though some RBPs have similar RNA-binding motifs, their IDRs may have evolved different physical properties that ensure specific spatiotemporal regulation This focus on continuous polyalanine tracts may be too restrictive, and the above analysis may have underestimated the importance of α-helix. A disrupted polyalanine tract may still contribute to self-assembly in combination with a few [G/S]-[F/Y/W]-[G/S] motifs or an increased prion-like propensity (Supplementary Figure S1)
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