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ALS/FTLD-Linked Mutations in FUS Glycine Residues Cause Accelerated Gelation and Reduced Interactions with Wild-Type FUS.
Rhine, Kevin; Makurath, Monika A; Liu, James; Skanchy, Sophie; Lopez, Christian; Catalan, Kevin F; Ma, Ye; Fare, Charlotte M; Shorter, James; Ha, Taekjip; Chemla, Yann R; Myong, Sua.
Afiliación
  • Rhine K; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
  • Makurath MA; Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Liu J; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Medical Genetics and Ophthalmic Genomics Unit, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Skanchy S; Department of Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
  • Lopez C; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
  • Catalan KF; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Biology, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA.
  • Ma Y; Department of Biomedical Engineering, Johns Hopkins Medical Institute, 615 N Wolfe St, Baltimore, MD 21231, USA.
  • Fare CM; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Shorter J; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Ha T; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Biophysics, Johns
  • Chemla YR; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
  • Myong S; Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, 3400 N Charles St, Baltimore, MD 21218, USA; Department of Physics, Center for the Physics of Living Cells, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Department of Biophysics, Johns
Mol Cell ; 80(4): 666-681.e8, 2020 11 19.
Article en En | MEDLINE | ID: mdl-33159856
The RNA-binding protein fused in sarcoma (FUS) can form pathogenic inclusions in neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Over 70 mutations in Fus are linked to ALS/FTLD. In patients, all Fus mutations are heterozygous, indicating that the mutant drives disease progression despite the presence of wild-type (WT) FUS. Here, we demonstrate that ALS/FTLD-linked FUS mutations in glycine (G) strikingly drive formation of droplets that do not readily interact with WT FUS, whereas arginine (R) mutants form mixed condensates with WT FUS. Remarkably, interactions between WT and G mutants are disfavored at the earliest stages of FUS nucleation. In contrast, R mutants physically interact with the WT FUS such that WT FUS recovers the mutant defects by reducing droplet size and increasing dynamic interactions with RNA. This result suggests disparate molecular mechanisms underlying ALS/FTLD pathogenesis and differing recovery potential depending on the type of mutation.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: ARN / Proteína FUS de Unión a ARN / Demencia Frontotemporal / Glicina / Esclerosis Amiotrófica Lateral / Mutación / Neuroblastoma Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: ARN / Proteína FUS de Unión a ARN / Demencia Frontotemporal / Glicina / Esclerosis Amiotrófica Lateral / Mutación / Neuroblastoma Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos