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Mechanistic View of hnRNPA2 Low-Complexity Domain Structure, Interactions, and Phase Separation Altered by Mutation and Arginine Methylation.
Ryan, Veronica H; Dignon, Gregory L; Zerze, Gül H; Chabata, Charlene V; Silva, Rute; Conicella, Alexander E; Amaya, Joshua; Burke, Kathleen A; Mittal, Jeetain; Fawzi, Nicolas L.
Afiliação
  • Ryan VH; Neuroscience Graduate Program, Brown University, Providence, RI 02912, USA.
  • Dignon GL; Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA.
  • Zerze GH; Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA.
  • Chabata CV; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
  • Silva R; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
  • Conicella AE; Graduate Program in Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02912, USA.
  • Amaya J; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
  • Burke KA; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA.
  • Mittal J; Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, PA 18015, USA.
  • Fawzi NL; Department of Molecular Pharmacology, Physiology, and Biotechnology, Brown University, Providence, RI 02912, USA. Electronic address: nicolas_fawzi@brown.edu.
Mol Cell ; 69(3): 465-479.e7, 2018 02 01.
Article em En | MEDLINE | ID: mdl-29358076
hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes-disease mutations and arginine methylation-on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form. Disease mutations D290V and P298L induce aggregation by enhancing and extending, respectively, the aggregation-prone region. Co-aggregating in disease inclusions, hnRNPA2 LC directly interacts with and induces phase separation of TDP-43. Conversely, arginine methylation reduces hnRNPA2 phase separation, disrupting arginine-mediated contacts. These results highlight the mechanistic role of specific LC domain interactions and modifications conserved across many hnRNP family members but altered by aggregation-causing pathological mutations.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article