2021年12月
C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers
Nature Communications
- 巻
- 12
- 号
- 1
- 記述言語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1038/s41467-021-25560-0
- 出版者・発行元
- Springer Science and Business Media LLC
<title>Abstract</title>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 <italic>C9orf72</italic> 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 <italic>C9orf72</italic>-related neurodegeneration.
- リンク情報
- ID情報
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- DOI : 10.1038/s41467-021-25560-0
- eISSN : 2041-1723