生物
核磷蛋白
内在无序蛋白质
细胞生物学
生物物理学
神经退行性变
生物化学
分子生物学
三核苷酸重复扩增
C9orf72
基因
医学
病理
等位基因
疾病
作者
Chen Chen,Yoshiaki Yamanaka,Koji Ueda,Peiying Li,Tamami Miyagi,Yuichiro Harada,Sayaka Tezuka,Shunji Narumi,Masahiro Sugimoto,Masahiko Kuroda,Yuhei Hayamizu,Kohsuke Kanekura
标识
DOI:10.1083/jcb.202103160
摘要
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.
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