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

DOI PDF 被引用文献9件 参考文献62件 オープンアクセス
  • Chen Chen
    Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
  • Yoshiaki Yamanaka
    Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
  • Koji Ueda
    Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan 3
  • Peiying Li
    Center for Biosystems Dynamics Research, RIKEN, Kanagawa, Japan 4
  • Tamami Miyagi
    Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
  • Yuichiro Harada
    Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
  • Sayaka Tezuka
    Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
  • Satoshi Narumi
    Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan 5
  • Masahiro Sugimoto
    Research and Development Center for Minimally Invasive Therapies, Tokyo Medical University, Tokyo, Japan 6
  • Masahiko Kuroda
    Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
  • Yuhei Hayamizu
    Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
  • Kohsuke Kanekura
    Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2

抄録

<jats:p>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.</jats:p>

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