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ID 117572
Nanaura, Hitoki Nara Medical University
Kawamukai, Honoka Hokkaido University|Tokushima University
Fujiwara, Ayano Ritsumeikan University
Uehara, Takeru Ritsumeikan University
Aiba, Yuichiro Nagoya University
Nakanishi, Mari Nara Medical University
Shiota, Tomo Nara Medical University
Hibino, Masaki Nagoya University
Wiriyasermkul, Pattama Nara Medical University|The Jikei University School of Medicine
Kikuchi, Sotaro Nara Medical University
Nagata, Riko Nara Medical University
Matsubayashi, Masaya Nara Medical University
Shinkai, Yoichi National Institute of Advanced Industrial Science and Technology
Niwa, Tatsuya Tokyo Institute of Technology
Mannen, Taro Ritsumeikan University
Morikawa, Naritaka Nara Medical University
Iguchi, Naohiko Nara Medical University
Kiriyama, Takao Nara Medical University
Morishima, Ken Kyoto University
Inoue, Rintaro Kyoto University
Sugiyama, Masaaki Kyoto University
Oda, Takashi Yokohama City University|Rikkyo University
Kodera, Noriyuki Kanazawa University
Toma-Fukai, Sachiko Nara Institute of Science and Technology
Sato, Mamoru Yokohama City University
Taguchi, Hideki Tokyo Institute of Technology
Nagamori, Shushi Nara Medical University|The Jikei University School of Medicine
Shoji, Osami Nagoya University
Ishimori, Koichiro Hokkaido University
Matsumura, Hiroyoshi Ritsumeikan University
Sugie, Kazuma Nara Medical University
Yoshizawa, Takuya Ritsumeikan University
Mori, Eiichiro Nara Medical University
Content Type
Journal Article
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.
Journal Title
Nature Communications
Springer Nature
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Published Date
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Institute of Advanced Medical Sciences