Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity
Abstract
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.
- Authors:
-
[4];
[4];
[1];
[8]
- Department of Pharmacology and Molecular Therapeutics Uniformed Services University Bethesda MD USA
- Neuroscience Graduate Program Brown University Providence RI USA
- Department of Molecular Pharmacology, Physiology, and Biotechnology Brown University Providence RI USA
- Department of Chemical and Biomolecular Engineering Lehigh University Bethlehem PA USA
- Johns Hopkins Mass Spectrometry and Proteomic Facility Johns Hopkins University Baltimore MD USA
- Graduate Program in Molecular Biology, Cell Biology and Biochemistry Brown University Providence RI USA
- Laboratory of Chemical Physics National Institutes of Health Bethesda MD USA
- Neuroscience Graduate Program Brown University Providence RI USA, Department of Molecular Pharmacology, Physiology, and Biotechnology Brown University Providence RI USA, Graduate Program in Molecular Biology, Cell Biology and Biochemistry Brown University Providence RI USA
- Publication Date:
- Research Org.:
- Lehigh Univ., Bethlehem, PA (United States); Brown Univ., Providence, RI (United States); Uniformed Services Univ., Bethesda, MD (United States); Johns Hopkins Univ., Baltimore, MD (United States); National Institutes of Health (NIH), Bethesda, MD (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); National Inst. of Health (NIH) (United States); Rhode Island Foundation (United States); National Science Foundation (NSF); Rhode Island Science and Technology Advisory Council (United States)
- OSTI Identifier:
- 1547127
- Alternate Identifier(s):
- OSTI ID: 1499120; OSTI ID: 1547129
- Grant/Contract Number:
- SC0013979; AC02‐05CH11231; S10RR027027; 1S10RR020923; S10RR02763; P20RR018728; P30RR031153; P30GM103410; R01GM118530; R35GM119790; P20GM104937; T32 MH020068; T32 GM07601; 20133966; TG‐MCB‐120014; 0554548; 1004057
- Resource Type:
- Published Article
- Journal Name:
- EMBO Journal
- Additional Journal Information:
- Journal Name: EMBO Journal Journal Volume: 36 Journal Issue: 20; Journal ID: ISSN 0261-4189
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; amyotrophic lateral sclerosis; frontotemporal dementia; intrinsically disordered protein; prion; ribonucleoprotein granule
Citation Formats
Monahan, Zachary, Ryan, Veronica H., Janke, Abigail M., Burke, Kathleen A., Rhoads, Shannon N., Zerze, Gül H., O'Meally, Robert, Dignon, Gregory L., Conicella, Alexander E., Zheng, Wenwei, Best, Robert B., Cole, Robert N., Mittal, Jeetain, Shewmaker, Frank, and Fawzi, Nicolas L. Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity. United Kingdom: N. p., 2017.
Web. doi:10.15252/embj.201696394.
Monahan, Zachary, Ryan, Veronica H., Janke, Abigail M., Burke, Kathleen A., Rhoads, Shannon N., Zerze, Gül H., O'Meally, Robert, Dignon, Gregory L., Conicella, Alexander E., Zheng, Wenwei, Best, Robert B., Cole, Robert N., Mittal, Jeetain, Shewmaker, Frank, & Fawzi, Nicolas L. Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity. United Kingdom. https://doi.org/10.15252/embj.201696394
Monahan, Zachary, Ryan, Veronica H., Janke, Abigail M., Burke, Kathleen A., Rhoads, Shannon N., Zerze, Gül H., O'Meally, Robert, Dignon, Gregory L., Conicella, Alexander E., Zheng, Wenwei, Best, Robert B., Cole, Robert N., Mittal, Jeetain, Shewmaker, Frank, and Fawzi, Nicolas L. Tue .
"Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity". United Kingdom. https://doi.org/10.15252/embj.201696394.
@article{osti_1547127,
title = {Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity},
author = {Monahan, Zachary and Ryan, Veronica H. and Janke, Abigail M. and Burke, Kathleen A. and Rhoads, Shannon N. and Zerze, Gül H. and O'Meally, Robert and Dignon, Gregory L. and Conicella, Alexander E. and Zheng, Wenwei and Best, Robert B. and Cole, Robert N. and Mittal, Jeetain and Shewmaker, Frank and Fawzi, Nicolas L.},
abstractNote = {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.},
doi = {10.15252/embj.201696394},
journal = {EMBO Journal},
number = 20,
volume = 36,
place = {United Kingdom},
year = {Tue Aug 08 00:00:00 EDT 2017},
month = {Tue Aug 08 00:00:00 EDT 2017}
}
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