The DOI matches its Crossref record; 83 of the 83 references it cites were found in a registry or an index.
Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity
Open accessAbstract
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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Alberti, S., Gladfelter, A., & Mittag, T. (2019) · Cell · doi:10.1016/j.cell.2018.12.035 · Cited by 2,856
Wang, J., Choi, J.-M., Holehouse, A. S., Lee, H. O., Zhang, X., Jahnel, M., Maharana, S., Lemaitre, R., Pozniakovsky, A., Drechsel, D., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.006 · Cited by 2,076
Tau protein liquid–liquid phase separation can initiate tau aggregation
Wegmann, S., Eftekharzadeh, B., Tepper, K., Zoltowska, K. M., Bennett, R. E., Dujardin, S., Laskowski, P. R., MacKenzie, D., Kamath, T., Commins, C., et al. (2018) · The EMBO Journal · doi:10.15252/embj.201798049 · Cited by 1,102
Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing
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Valence and patterning of aromatic residues determine the phase behavior of prion-like domains
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Metadata
- Authors
- Monahan, Z., Ryan, V. H., Janke, A. M., Burke, K. A., Rhoads, S. N., Zerze, G. H., O'Meally, R., Dignon, G. L., Conicella, A. E., Zheng, W., Best, R. B., Cole, R. N., Mittal, J., Shewmaker, F., & Fawzi, N. L.
- Venue
- The EMBO Journal
- Published
- 2017-08-08
- Volume
- 36
- Issue
- 20
- Pages
- 2951-2967
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- OpenAlex
- W2742396220
- Cited by
- 684
- References
- 83
- FWCI
- 35.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Monahan, Z., Ryan, V. H., Janke, A. M., Burke, K. A., Rhoads, S. N., Zerze, G. H., O'Meally, R., Dignon, G. L., Conicella, A. E., Zheng, W., Best, R. B., Cole, R. N., Mittal, J., Shewmaker, F., & Fawzi, N. L. (2017). Phosphorylation of the FUS low‐complexity domain disrupts phase separation, aggregation, and toxicity. The EMBO Journal. https://doi.org/10.15252/embj.201696394
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