The DOI matches its Crossref record; 82 of the 82 references it cites were found in a registry or an index.
A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing
Open accessAbstract
TDP‐43 is an RNA‐binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Although best known for its predominantly disordered C‐terminal domain which mediates ALS inclusions, TDP‐43 has a globular N‐terminal domain (NTD). Here, we show that TDP‐43 NTD assembles into head‐to‐tail linear chains and that phosphomimetic substitution at S48 disrupts TDP‐43 polymeric assembly, discourages liquid–liquid phase separation (LLPS) in vitro, fluidizes liquid–liquid phase separated nuclear TDP‐43 reporter constructs in cells, and disrupts RNA splicing activity. Finally, we present the solution NMR structure of a head‐to‐tail NTD dimer comprised of two engineered variants that allow saturation of the native polymerization interface while disrupting higher‐order polymerization. These data provide structural detail for the established mechanistic role of the well‐folded TDP‐43 NTD in splicing and link this function to LLPS. In addition, the fusion‐tag solubilized, recombinant form of TDP‐43 full‐length protein developed here will enable future phase separation and in vitro biochemical assays on TDP‐43 function and interactions that have been hampered in the past by TDP‐43 aggregation. The N‐terminal globular domain (NTD) of TDP‐43 forms linear polymers whose disruption by phosphomimetic substitution reduces TDP‐43 liquid‐liquid phase separation and RNA splicing function. Structural and functional analyses of ALS‐related protein TDP43 illustrates its higher order organisation and links splicing activity with the ability to undergo liquid–liquid phase separation.
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Self-citationMolecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis
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RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43
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McGurk, L., Gomes, E., Guo, L., Mojsilovic-Petrovic, J., Tran, V., Kalb, R. G., Shorter, J., & Bonini, N. M. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.07.002 · Cited by 409
Metadata
- Authors
- Wang, A., Conicella, A. E., Schmidt, H. B., Martin, E. W., Rhoads, S. N., Reeb, A. N., Nourse, A., Ramirez Montero, D., Ryan, V. H., Rohatgi, R., Shewmaker, F., Naik, M. T., Mittag, T., Ayala, Y. M., & Fawzi, N. L.
- Venue
- The EMBO Journal
- Published
- 2018-02-09
- Volume
- 37
- Issue
- 5
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- OpenAlex
- W2786688711
- Cited by
- 444
- References
- 82
- FWCI
- 25.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Wang, A., Conicella, A. E., Schmidt, H. B., Martin, E. W., Rhoads, S. N., Reeb, A. N., Nourse, A., Ramirez Montero, D., Ryan, V. H., Rohatgi, R., Shewmaker, F., Naik, M. T., Mittag, T., Ayala, Y. M., & Fawzi, N. L. (2018). A single N‐terminal phosphomimic disrupts TDP‐43 polymerization, phase separation, and RNA splicing. The EMBO Journal. https://doi.org/10.15252/embj.201797452
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