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

Hitoki Nanaura, Honoka Kawamukai, Ayano Fujiwara, Takeru Uehara, Yuichiro Aiba, Mari Nakanishi, Tomo Shiota, Masaki Hibino, Pattama Wiriyasermkul, Sotaro Kikuchi, Riko Nagata, Masaya Matsubayashi, Yoichi Shinkai, Tatsuya Niwa, Taro Mannen, Naritaka Morikawa, Naohiko Iguchi, Takao Kiriyama, Ken Morishima, Rintaro Inoue, Masaaki Sugiyama, Takashi Oda, Noriyuki Kodera, Sachiko Toma-Fukai, Mamoru Sato, Hideki Taguchi, Shushi Nagamori, Osami Shoji, Koichiro Ishimori, Hiroyoshi Matsumura, Kazuma Sugie, Tomohide Saio (), Takuya Yoshizawa () and Eiichiro Mori ()
Additional contact information
Hitoki Nanaura: Nara Medical University
Honoka Kawamukai: Hokkaido University
Ayano Fujiwara: Ritsumeikan University
Takeru Uehara: Ritsumeikan University
Yuichiro Aiba: Nagoya University
Mari Nakanishi: Nara Medical University
Tomo Shiota: Nara Medical University
Masaki Hibino: Nagoya University
Pattama Wiriyasermkul: Nara Medical University
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
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
Osami Shoji: Nagoya University
Koichiro Ishimori: Hokkaido University
Hiroyoshi Matsumura: Ritsumeikan University
Kazuma Sugie: Nara Medical University
Tomohide Saio: Tokushima University
Takuya Yoshizawa: Ritsumeikan University
Eiichiro Mori: Nara Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25560-0

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