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

Hitoki Nanaura, Honoka Kawamukai, Ayano Fujiwara, Takeru Uehara, Mari Nakanishi, Tomo Shiota, Masaki Hibino, Yuichiro Aiba, Pattama Wiriyasermkul, Sotaro Kikuchi, Riko Nagata, Masaya Matsubayashi, Shushi Nagamori, Osami Shoji, Koichiro Ishimori, Hiroyoshi Matsumura, Kazuma Sugie, Tomohide Saio, Takuya Yoshizawa, Eiichiro Mori
doi: https://doi.org/10.1101/812099
Hitoki Nanaura
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
2Department of Neurology, Nara Medical University, Kashihara, Nara, Japan
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Honoka Kawamukai
3Graduate School of Chemical Sciences and Engineering, Hokkaido University, Sapporo, Hokkaido, Japan
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Ayano Fujiwara
4College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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Takeru Uehara
4College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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Mari Nakanishi
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
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Tomo Shiota
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
2Department of Neurology, Nara Medical University, Kashihara, Nara, Japan
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Masaki Hibino
5Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan
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Yuichiro Aiba
5Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan
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Pattama Wiriyasermkul
6Laboratory of Bio-Molecular Dynamics, Department of Collaborative Research, Nara Medical University, Kashihara, Nara, Japan
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Sotaro Kikuchi
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
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Riko Nagata
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
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Masaya Matsubayashi
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
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Shushi Nagamori
6Laboratory of Bio-Molecular Dynamics, Department of Collaborative Research, Nara Medical University, Kashihara, Nara, Japan
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Osami Shoji
5Department of Chemistry, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan
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Koichiro Ishimori
7Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido, Japan
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Hiroyoshi Matsumura
4College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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Kazuma Sugie
2Department of Neurology, Nara Medical University, Kashihara, Nara, Japan
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Tomohide Saio
7Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido, Japan
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  • For correspondence: saio@sci.hokudai.ac.jp
Takuya Yoshizawa
4College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
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  • For correspondence: t-yosh@fc.ritsumei.ac.jp
Eiichiro Mori
1Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan
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  • For correspondence: saio@sci.hokudai.ac.jp
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ABSTRACT

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.

  • The abbrevations used are

    LC
    low-complexity
    ALS
    amyotrophic lateral sclerosis
    NLS
    nuclear localization signal
    PY-NLS
    proline-tyrosine nuclear localization signal
    FUS
    fused in sarcoma
    hnRNP
    heterogeneous nuclear ribonucleo-protein
    LC polymer
    labile cross-β polymer formed from LC-domains
    MSP
    multisystem proteinopathy
    FTD
    frontotemporal dementia
    PR
    proline:arginine
    GR
    glycine:arginine
    FG
    phenylalanine:glycine
    MBP
    maltose binding protein
    ITC
    isothermal titration calorimetry
    NMR
    nuclear magnetic resonance
    TROSY
    methyl-transverse relaxation-optimized spectroscopy
    MD
    molecular dynamics
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    Posted October 21, 2019.
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    Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target Kapβ2 and dysregulate phase separation of low-complexity domains
    Hitoki Nanaura, Honoka Kawamukai, Ayano Fujiwara, Takeru Uehara, Mari Nakanishi, Tomo Shiota, Masaki Hibino, Yuichiro Aiba, Pattama Wiriyasermkul, Sotaro Kikuchi, Riko Nagata, Masaya Matsubayashi, Shushi Nagamori, Osami Shoji, Koichiro Ishimori, Hiroyoshi Matsumura, Kazuma Sugie, Tomohide Saio, Takuya Yoshizawa, Eiichiro Mori
    bioRxiv 812099; doi: https://doi.org/10.1101/812099
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    Toxic PR poly-dipeptides encoded by the C9orf72 repeat expansion target Kapβ2 and dysregulate phase separation of low-complexity domains
    Hitoki Nanaura, Honoka Kawamukai, Ayano Fujiwara, Takeru Uehara, Mari Nakanishi, Tomo Shiota, Masaki Hibino, Yuichiro Aiba, Pattama Wiriyasermkul, Sotaro Kikuchi, Riko Nagata, Masaya Matsubayashi, Shushi Nagamori, Osami Shoji, Koichiro Ishimori, Hiroyoshi Matsumura, Kazuma Sugie, Tomohide Saio, Takuya Yoshizawa, Eiichiro Mori
    bioRxiv 812099; doi: https://doi.org/10.1101/812099

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