Fig. 1

Schematic of TDP-43, FET proteins, hnRNPA1 and hnRNPA2 domains and their interaction with importins. To regulate nuclear import and phase transition of RBPs, TNPO1 binds the PY-NLS of FUS and, with a lower affinity, its RGG domains, while KPNB1 interacts with both the NLS (via KPNA or importin-α) and PrLD of TDP-43. Of note, most ALS disease-causing mutations are located in the PY-NLS and PrLD of FUS and TDP-43, respectively. Lysine acetylation sites that regulate phase separation of these prion-like RBPs are also highlighted. Other importins also bind the RGG domains of FUS and PrLD of TDP-43. Thus far, only TNPO1 has been shown to bind the PY-NLS of EWSR1, TAF15, hnRNPA1 and hnRNPA2. The *A90V mutation in TARDBP is also found in the healthy population. Brackets indicate prion-like domains (PrLDs) as defined by their amino acid composition [63]. NLS = nuclear localization signal; NTD = N-terminal domain; P/Y = Pro-Tyr nuclear localization signal; PrLD = prion-like domain; QSYG-rich = Gln, Ser, Tyr, and Gly-rich domain; RGG = Arg-Gly-Gly repeat domain; RRM = RNA-recognition motif; ZnF = zinc finger domain. Created with BioRender.com