Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine
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- Chen Chen
- Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
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- Yoshiaki Yamanaka
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
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- Koji Ueda
- Cancer Proteomics Group, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan 3
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- Peiying Li
- Center for Biosystems Dynamics Research, RIKEN, Kanagawa, Japan 4
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- Tamami Miyagi
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
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- Yuichiro Harada
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
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- Sayaka Tezuka
- Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
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- Satoshi Narumi
- Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan 5
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- Masahiro Sugimoto
- Research and Development Center for Minimally Invasive Therapies, Tokyo Medical University, Tokyo, Japan 6
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- Masahiko Kuroda
- Department of Molecular Pathology, Tokyo Medical University, Tokyo, Japan 2
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- Yuhei Hayamizu
- Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan 1
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- 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>
収録刊行物
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- Journal of Cell Biology
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Journal of Cell Biology 220 (11), 2021-09-09
Rockefeller University Press
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キーワード
詳細情報 詳細情報について
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- CRID
- 1364233269156631040
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- ISSN
- 15408140
- 00219525
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- データソース種別
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- Crossref
- KAKEN