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

• DOI: 10.1038/s41467-021-25560-0
• Publication Date: 2021-09-06T10:04:08Z
• Authors: Hitoki Nanaura; Honoka Kawamukai; Ayano Fujiwara; Takeru Uehara; Yuichiro Aiba; Mari Nakanishi; Tomo Shiota; Masaki Hibino; Pattama Wiriyaser...; 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; Eiichiro Mori
• Keywords: Isothermal Titration Calorimetry; NLS; C9ORF72

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 deficit. However, the molecular basis for toxicity toward function as modifiers remains unidentified. Here we show that impede ability to RBPs. Isothermal titration calorimetry size-exclusion chromatography revealed proline:arginine (PR) tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The magnetic resonances Kapβ2 perturbed PR partially overlapped those designed NLS peptide, suggesting target binding site Kapβ2. findings offer mechanistic insights into how are disabled in -related neurodegeneration.