N‐terminal acetylation modestly enhances phase separation and reduces aggregation of the low‐complexity domain of RNA‐binding protein fused in sarcoma

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  • Anna S. Bock
    Graduate Program in Biotechnology Brown University Providence Rhode Island USA
  • Anastasia C. Murthy
    Graduate Program in Molecular Biology, Cell Biology, and Biochemistry Brown University Providence Rhode Island USA
  • Wai Shing Tang
    Graduate Program in Physics Brown University Providence Rhode Island USA
  • Nina Jovic
    Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem Pennsylvania USA
  • Frank Shewmaker
    Department of Biochemistry Uniformed Services University Bethesda Maryland USA
  • Jeetain Mittal
    Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem Pennsylvania USA
  • Nicolas L. Fawzi
    The Robert J and Nancy D Carney Institute for Brain Science & Department of Molecular Pharmacology, Physiology, and Biotechnology Brown University Providence Rhode Island USA

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<jats:title>Abstract</jats:title><jats:p>The RNA‐binding protein fused in sarcoma (FUS) assembles via liquid–liquid phase separation (LLPS) into functional RNA granules and aggregates in amyotrophic lateral sclerosis associated neuronal inclusions. Several studies have demonstrated that posttranslational modification (PTM) can significantly alter FUS phase separation and aggregation, particularly charge‐altering phosphorylation of the nearly uncharged N‐terminal low complexity domain of FUS (FUS LC). However, the occurrence and impact of N‐terminal acetylation on FUS phase separation remains unexplored, even though N‐terminal acetylation is the most common PTM in mammals and changes the charge at the N‐terminus. First, we find that FUS is predominantly acetylated in two human cell types and stress conditions. Next, we show that recombinant FUS LC can be acetylated when co‐expressed with the NatA complex in <jats:italic>Escherichia coli</jats:italic>. Using NMR spectroscopy, we find that N‐terminal acetylated FUS LC (FUS LC Nt‐Ac) does not notably alter monomeric FUS LC structure or motions. Despite no difference in structure, Nt‐Ac‐FUS LC phase separates more avidly than unmodified FUS LC. More importantly, N‐terminal acetylation of FUS LC reduces aggregation. Our findings highlight the importance of N‐terminal acetylation of proteins that undergo physiological LLPS and pathological aggregation.</jats:p>

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