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. 2022;19(1):622-635.
doi: 10.1080/15476286.2022.2066336. Epub 2021 Dec 31.

F/YGG-motif is an intrinsically disordered nucleic-acid binding motif

Joris Van Lindt  1   2 , Tamas Lazar  1   2 , Donya Pakravan  3   4 , Manon Demulder  1   2 , Attila Meszaros  1   2 , Ludo Van Den Bosch  3   4 , Dominique Maes  2 , Peter Tompa  1   2   5
Affiliations

F/YGG-motif is an intrinsically disordered nucleic-acid binding motif

Joris Van Lindt et al. RNA Biol. 2022.

Abstract

Heterogeneous nuclear ribonucleoproteins (hnRNP) function in RNA processing, have RNA-recognition motifs (RRMs) and intrinsically disordered, low-complexity domains (LCDs). While RRMs are drivers of RNA binding, there is only limited knowledge about the RNA interaction by the LCD of some hnRNPs. Here, we show that the LCD of hnRNPA2 interacts with RNA via an embedded Tyr/Gly-rich region which is a disordered RNA-binding motif. RNA binding is maintained upon mutating tyrosine residues to phenylalanines, but abrogated by mutating to alanines, thus we term the RNA-binding region 'F/YGG motif'. The F/YGG motif can bind a broad range of structured (e.g. tRNA) and disordered (e.g. polyA) RNAs, but not rRNA. As the F/YGG otif can also interact with DNA, we consider it a general nucleic acid-binding motif. hnRNPA2 LCD can form dense droplets, by liquid-liquid phase separation (LLPS). Their formation is inhibited by RNA binding, which is mitigated by salt and 1,6-hexanediol, suggesting that both electrostatic and hydrophobic interactions feature in the F/YGG motif. The D290V mutant also binds RNA, which interferes with both LLPS and aggregation thereof. We found homologous regions in a broad range of RNA- and DNA-binding proteins in the human proteome, suggesting that the F/YGG motif is a general nucleic acid-interaction motif.

Keywords: Liquid-liquid phase separation; disordered proteins; low complexity domain; nucleic acid interaction; sequence motif.

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Conflict of interest statement

No potential conflict of interest was reported by the authors.

Figures

Figure 1.
Figure 1.
hnRNPA2 LCD interacts with RNA.
Figure 2.
Figure 2.
hnRNPA2 LCD undergoes LLPS and recruits RNA to droplets.
Figure 3.
Figure 3.
RNA increases the saturation concentration of the LLPS of hnRNPA2 LCD.
Figure 4.
Figure 4.
hnRNPA2 LCD interacts with many types of RNA and also DNA.
Figure 5.
Figure 5.
Salt, 1,6 hexanediol and RNAse A reverse the LLPS-inhibitory effect of RNA.
Figure 6.
Figure 6.
The effect of RNA on the LLPS of ALS-related D290V mutant of hnRNPA2 LCD.
Figure 7.
Figure 7.
Conservation of YGG motif in human proteins.
See this image and copyright information in PMC

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