Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity
By Zachary T. Monahan, Veronica H. Ryan, Abigail M. Janke, K. Burke, S. Rhoads, Gül H. Zerze, Robert N. O’Meally, G. Dignon, Alexander E. Conicella, Wenwei Zheng and 5 more. EMBO Journal, 2017
611 citations recorded by the source corpus.
Neuronal inclusions of aggregated RNA‐binding protein fused in sarcoma (FUS) are hallmarks of ALS and frontotemporal dementia subtypes. Intriguingly, FUS's nearly uncharged, aggregation‐prone, yeast prion‐like, low sequence‐complexity domain (LC) is known to be targeted for phosphorylation. Here we map in vitro and in‐cell phosphorylation sites across FUS LC. We show that both phosphorylation and phosphomimetic variants reduce its aggregation‐prone/prion‐like character, disrupting FUS phase separation in the presence of RNA or salt and reducing FUS propensity to aggregate. Nuclear magnetic resonance spectroscopy demonstrates the intrinsically disordered structure of FUS LC is preserved after phosphorylation; however, transient domain collapse and self‐interaction are reduced by phosphomimetics. Moreover, we show that phosphomimetic FUS reduces aggregation in human and yeast cell models, and can ameliorate FUS‐associated cytotoxicity. Hence, post‐translational modification may be a mechanism by which cells control physiological assembly and prevent pathological protein aggregation, suggesting a potential treatment pathway amenable to pharmacologic modulation.
Subfields: Materials Chemistry, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/37eb0b994f7b9f5bee5b9e4501382a0e7cdc548c
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In Materials Chemistry
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In Molecular Biology
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Citations in the corpus
- Protein Phase Separation: A New Phase in Cell Biology (2018, background): “separation [12, 52, 91, 92], and the same holds true for arginine methylation [49, 93] and sumoylation”
- A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, neutral): “Productive interactions among tyrosine and arginine residues are regulated by complementary electrostatic interactions involving negatively charged amino acids, which reduce self-interaction among the PLDs (Monahan et al., 2017; Murray et al., 2017) and promote interactions among the PLDs and RBDs.”
- Liquid-Liquid Phase Separation in Disease. (2019, background): “Indeed, there is increasing evidence for regulation of phase separation by PTMs (71), such as phosphorylation (91, 109) and methylation (72).”