並列タイトル等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
一般注記type:Thesis
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.
博士（医学）・甲第826号・令和4年3月15日
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identifier:Nature communications Vol.12 No.1 Article No.5301 (2021 Sep)
identifier:20411723
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4009
identifier:Nature communications, 12(1): Article No.5301
DOIinfo:doi/10.1038/s41467-021-25560-0
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