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C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers

Author

Listed:
  • Hitoki Nanaura

    (Nara Medical University
    Nara Medical University)

  • Honoka Kawamukai

    (Hokkaido University
    Tokushima University)

  • Ayano Fujiwara

    (Ritsumeikan University)

  • Takeru Uehara

    (Ritsumeikan University)

  • Yuichiro Aiba

    (Nagoya University)

  • Mari Nakanishi

    (Nara Medical University)

  • Tomo Shiota

    (Nara Medical University
    Nara Medical University)

  • Masaki Hibino

    (Nagoya University)

  • Pattama Wiriyasermkul

    (Nara Medical University
    The Jikei University School of Medicine)

  • Sotaro Kikuchi

    (Nara Medical University)

  • Riko Nagata

    (Nara Medical University)

  • Masaya Matsubayashi

    (Nara Medical University)

  • Yoichi Shinkai

    (National Institute of Advanced Industrial Science and Technology (AIST))

  • Tatsuya Niwa

    (Tokyo Institute of Technology)

  • Taro Mannen

    (Ritsumeikan University)

  • Naritaka Morikawa

    (Nara Medical University)

  • Naohiko Iguchi

    (Nara Medical University)

  • Takao Kiriyama

    (Nara Medical University)

  • Ken Morishima

    (Kyoto University)

  • Rintaro Inoue

    (Kyoto University)

  • Masaaki Sugiyama

    (Kyoto University)

  • Takashi Oda

    (Yokohama City University
    Rikkyo University)

  • Noriyuki Kodera

    (Kanazawa University)

  • Sachiko Toma-Fukai

    (Nara Institute of Science and Technology)

  • Mamoru Sato

    (Yokohama City University)

  • Hideki Taguchi

    (Tokyo Institute of Technology)

  • Shushi Nagamori

    (Nara Medical University
    The Jikei University School of Medicine)

  • Osami Shoji

    (Nagoya University)

  • Koichiro Ishimori

    (Hokkaido University
    Hokkaido University)

  • Hiroyoshi Matsumura

    (Ritsumeikan University)

  • Kazuma Sugie

    (Nara Medical University)

  • Tomohide Saio

    (Tokushima University
    Tokushima University)

  • Takuya Yoshizawa

    (Ritsumeikan University)

  • Eiichiro Mori

    (Nara Medical University
    Nara Medical University)

Abstract

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The nuclear magnetic resonances of Kapβ2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapβ2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.

Suggested Citation

  • Hitoki Nanaura & Honoka Kawamukai & Ayano Fujiwara & Takeru Uehara & Yuichiro Aiba & Mari Nakanishi & Tomo Shiota & Masaki Hibino & Pattama Wiriyasermkul & Sotaro Kikuchi & Riko Nagata & Masaya Matsub, 2021. "C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25560-0
    DOI: 10.1038/s41467-021-25560-0
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