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Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target Kapβ2 and dysregulate phase separation of low-complexity domains

Low-complexity (LC) domains of proteins are found in about one fifth of human proteome, and a group of LC-domains form labile cross-β polymers and liquid-like droplets. Polymers and droplets formed from LC-domains are dynamically regulated by posttranslational modifications and molecular chaperones including nuclear transport receptors. Repeat expansion in the first intron of a gene designated C9orf72, which is the most prevalent form of familial amyotrophic lateral sclerosis (ALS), causes nucleocytoplasmic transport deficit, however, the detailed mechanism remains unsolved. Here we show that the proline:arginine (PR) poly-dipeptides encoded by the C9orf72 repeat expansion bound nuclear transport receptor Kapβ2 through its nuclear localization signal (NLS) recognition motif, and inhibited the ability of Kapβ2 to melt fused in sarcoma (FUS) droplets by competing interaction with FUS. The findings in this study offer mechanistic insights as to how the C9orf72 repeat expansion disables nucleocytoplasmic transport and causes neurodegenerative diseases.