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

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.

doi:10.15252/embj.201696394

Title: Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

Journal Article · Tue Aug 08 00:00:00 EDT 2017 · EMBO Journal

DOI:https://doi.org/10.15252/embj.201696394· OSTI ID:1547127

Monahan, Zachary ^[1]; Ryan, Veronica H. ^[2]; Janke, Abigail M. ^[3]; Burke, Kathleen A. ^[3]; Rhoads, Shannon N. ^[1]; Zerze, Gül H. ^[4]; O'Meally, Robert ^[5];

^[4]; Conicella, Alexander E. ^[6]; Zheng, Wenwei ^[7]; Best, Robert B. ^[7]; Cole, Robert N. ^[5];

^[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

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.

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Research Organization:: 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 Organization:: 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)

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

OSTI ID:: 1547127

Alternate ID(s):: OSTI ID: 1499120; OSTI ID: 1547129

Journal Information:: EMBO Journal, Journal Name: EMBO Journal Vol. 36 Journal Issue: 20; ISSN 0261-4189

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United Kingdom

Language:: English

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Cited by: 410 works

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amyotrophic lateral sclerosis
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Title: Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity

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