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. 2022 May;31(5):e4317.
doi: 10.1002/pro.4317.

The return of the rings: Evolutionary convergence of aromatic residues in the intrinsically disordered regions of RNA-binding proteins for liquid-liquid phase separation

Wen-Lin Ho  1 , Jie-Rong Huang  1   2   3
Affiliations

The return of the rings: Evolutionary convergence of aromatic residues in the intrinsically disordered regions of RNA-binding proteins for liquid-liquid phase separation

Wen-Lin Ho et al. Protein Sci. 2022 May.

Abstract

Aromatic residues appeared relatively late in the evolution of protein sequences to stabilize the globular proteins' folding core and are less in the intrinsically disordered regions (IDRs). Recent advances in protein liquid-liquid phase separation (LLPS) studies have also shown that aromatic residues in IDRs often act as "stickers" to promote multivalent interactions in forming higher-order oligomers. To study how general these structure-promoting residues are in IDRs, we compared levels of sequence disorder in RNA binding proteins (RBPs), which are often found to undergo LLPS, and the human proteome. We found that aromatic residues appear more frequently than expected in the IDRs of RBPs and, through multiple sequence alignment analysis, those aromatic residues are often conserved among chordates. Using TDP-43, FUS, and some other well-studied LLPS proteins as examples, the conserved aromatic residues are important to their LLPS-related functions. These analyses suggest that aromatic residues may have contributed twice to evolution: stabilizing structured proteins and assembling biomolecular condensates.

Keywords: RNA-binding proteins; biomolecular condensates; intrinsically disordered proteins; liquid-liquid phase separation; membraneless organelle.

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Figures

FIGURE 1
FIGURE 1
Prevalence of disorder and disorder odds ratios relative to the human proteome by amino acid type for RNA‐binding proteins. (a) Proportion of proteins with disordered regions longer than 30, 40, or 50 consecutive residues, as predicted using different algorithms, in the human proteome (left column), RNA‐binding proteins (middle column), and mRNA binding proteins (right column). (b) Log‐odds ratios relative to the human proteome of being in an intrinsically disordered region for amino acids in RNA binding proteins (RBPs) (left) and mRBPs (right). The dashed lines indicate the average value over all amino acid types. The dots represent the values obtained for randomly selected (negative control) subsamples (N = 1,542 for RBPs and N = 689 for mRBP, the same numbers as considered in the main analysis) of the human proteome
FIGURE 2
FIGURE 2
Sequence conservation in example proteins with highly conserved aromatic residues. (a) TDP‐43, (b) FUS, NUP153, and TNRC6A. (Upper panels) Levels of sequence conservation are quantified by the Jensen–Shannon divergence score and normalized using the Z‐score function (the mean of all values toward chordates is 0; the value in the y‐axes is the standard deviation, positive values mean more conserved.). Levels of conservation in chordates (dark blue), vertebrates (gray), tetrapods (gray), and mammals (light blue), plotted versus the corresponding residue number in the human sequence. Predicted disordered regions longer than 40 residues are indicated with red bars. Aromatic residues are labeled on the chordate line: Phe (orange), Trp (purple), Tyr (yellow). (a) The three arrows indicate tryptophans experimentally identified as being crucial to liquid–liquid phase separation; the transient α‐helical region that also contributes to self‐assembly is also labeled. (b) The colored horizontal curly brackets indicate highly conserved aromatic‐residue‐rich regions. (Lower panels) Average levels of conservation as a function of decreasing taxonomic rank for amino‐acid types in regions predicted to be disordered (indicated by red bars in the upper panel)
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