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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/4009

Title: C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers.
Other Titles: C9orf72リピート異常伸長より生じる毒性ペプチドは相分離制御因子の機能を阻害する
Authors: Nanaura, Hitoki
Kawamukai, Honoka
Fujiwara, Ayano
Uehara, Takeru
Aiba, Yuichiro
Nakanishi, Mari
Shiota, Tomo
Hibino, Masaki
Wiriyasermkul, Pattama
Kikuchi, Sotaro
Nagata, Riko
Matsubayashi, Masaya
Shinkai, Yoichi
Niwa, Tatsuya
Mannen, Taro
Morikawa, Naritaka
Iguchi, Naohiko
Kiriyama, Takao
Morishima, Ken
Inoue, Rintaro
Sugiyama, Masaaki
Oda, Takashi
Kodera, Noriyuki
Toma-Fukai, Sachiko
Sato, Mamoru
Taguchi, Hideki
Nagamori, Shushi
Shoji, Osami
Ishimori, Koichiro
Matsumura, Hiroyoshi
Sugie, Kazuma
Saio, Tomohide
Yoshizawa, Takuya
Mori, Eiichiro
Keywords: Biophysical chemistry
Intrinsically disordered proteins
Neurodegeneration
Issue Date: 6-Sep-2021
Publisher: Springer Nature
Citation: Nature communications Vol.12 No.1 Article No.5301 (2021 Sep)
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.
Description: 博士(医学)・甲第826号・令和4年3月15日
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
URI: http://hdl.handle.net/10564/4009
ISSN: 20411723
DOI: https://doi.org/10.1038/s41467-021-25560-0
Academic Degrees and number: 24601A826
Degree-granting date: 2022-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2021年度

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