論文

査読有り 国際誌
2021年11月1日

Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine

Journal of Cell Biology
  • Chen Chen
  • ,
  • Yoshiaki Yamanaka
  • ,
  • Koji Ueda
  • ,
  • Peiying Li
  • ,
  • Tamami Miyagi
  • ,
  • Yuichiro Harada
  • ,
  • Sayaka Tezuka
  • ,
  • Satoshi Narumi
  • ,
  • Masahiro Sugimoto
  • ,
  • Masahiko Kuroda
  • ,
  • Yuhei Hayamizu
  • ,
  • Kohsuke Kanekura

220
11
開始ページ
e202103160
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1083/jcb.202103160
出版者・発行元
Rockefeller University Press

Arg (R)-rich dipeptide repeat proteins (DPRs; poly(PR): Pro-Arg and poly(GR): Gly-Arg), encoded by a hexanucleotide expansion in the C9ORF72 gene, induce neurodegeneration in amyotrophic lateral sclerosis (ALS). Although R-rich DPRs undergo liquid–liquid phase separation (LLPS), which affects multiple biological processes, mechanisms underlying LLPS of DPRs remain elusive. Here, using in silico, in vitro, and in cellulo methods, we determined that the distribution of charged Arg residues regulates the complex coacervation with anionic peptides and nucleic acids. Proteomic analyses revealed that alternate Arg distribution in poly(PR) facilitates entrapment of proteins with acidic motifs via LLPS. Transcription, translation, and diffusion of nucleolar nucleophosmin (NPM1) were impaired by poly(PR) with an alternate charge distribution but not by poly(PR) variants with a consecutive charge distribution. We propose that the pathogenicity of R-rich DPRs is mediated by disturbance of proteins through entrapment in the phase-separated droplets via sequence-controlled multivalent protein–protein interactions.

リンク情報
DOI
https://doi.org/10.1083/jcb.202103160
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/34499080
URL
http://rupress.org/jcb/article-pdf/doi/10.1083/jcb.202103160/1422265/jcb_202103160.pdf
ID情報
  • DOI : 10.1083/jcb.202103160
  • ISSN : 0021-9525
  • eISSN : 1540-8140
  • PubMed ID : 34499080

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