Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity

Topic: Brain proteins, microglia and lab models

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.

@article{monahan2017-28790177,
  author  = {Monahan, Z. and Ryan, V. H. and Janke, A. M. and Burke, K. A. and Rhoads, S. N. and Zerze, G. H. and O'Meally, R. and Dignon, G. L. and others},
  title   = {{Phosphorylation of the FUS low-complexity domain disrupts phase separation, aggregation, and toxicity}},
  journal = {The EMBO journal},
  year    = {2017},
  doi     = {10.15252/embj.201696394},
  pmid    = {28790177},
  url     = {https://doi.org/10.15252/embj.201696394}
}

Key findings

• 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.

Why it matters

FUS is a protein whose clumps inside nerve cells are a hallmark of ALS and some forms of frontotemporal dementia; this lab study found that adding phosphate groups to its sticky "low-complexity" region, or mutations that mimic them, made the protein less likely to phase-separate and aggregate. In human and yeast cells, the phosphate-mimicking version of FUS aggregated less and "can ameliorate FUS-associated cytotoxicity." The authors suggest this is a "potential treatment pathway amenable to pharmacologic modulation," but no drug was tested and the study did not look at Alzheimer's disease.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.15252/embj.201696394
• PubMed: 28790177
• Original source →
• Free full text: The EMBO Journal →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• A new subtype of frontotemporal lobar degeneration with FUS pathology Brain : a journal of neurology · 2009-08-11 · usefulness score 58/100 · Lewy body dementia
• Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization Cell · 2015-09-01 · usefulness score 56/100 · Lewy body dementia
• C9orf72 Dipeptide Repeats Impair the Assembly, Dynamics, and Function of Membrane-Less Organelles Cell · 2016-10-01 · usefulness score 54/100 · Lewy body dementia
• Molecular determinants and genetic modifiers of aggregation and toxicity for the ALS disease protein FUS/TLS PLoS biology · 2011-04-26 · usefulness score 52/100 · Lewy body dementia
• The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease Brain research · 2012-01-21 · usefulness score 52/100 · Lewy body dementia

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• Molecular Mechanisms of Protein Aggregation in ALS-FTD: Focus on TDP-43 and Cellular Protective Responses Cells · 2025-05-08 · usefulness score 44/100 · Brain tissue and pathology
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