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ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain
Open accessAbstract
Summary RNA-binding protein TDP-43 mediates essential RNA processing but forms cytoplasmic neuronal inclusions via its C-terminal domain (CTD) in amyotrophic lateral sclerosis (ALS). It remains unclear if aggregated TDP-43 is neurotoxic and if ~50 ALS-associated missense mutations in TDP-43 CTD promote aggregation, or if loss-of-normal-function plays a role in disease. Recent work points to the ability of related proteins to assemble into functional phase-separated ribonucleoprotein granules via their structurally-disordered “prion-like” domains. Here, we provide atomic details on the structure and assembly of the low-complexity CTD of TDP-43 into liquid-liquid phase-separated in vitro granules and demonstrate that ALS-associated variants disrupt interactions within granules. Using NMR spectroscopy, simulation, and microscopy, we find that a subregion cooperatively but transiently folds into a helix that mediates TDP-43 phase separation. ALS-associated mutations disrupt phase separation by inhibiting interaction and helical stabilization. Therefore, ALS-associated mutations can disrupt TDP-43 interactions, affecting function beyond encouraging aggregation.
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Metadata
- Authors
- Conicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L.
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 24
- Issue
- 9
- Pages
- 1537-1549
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W2510545519
- Cited by
- 857
- References
- 6
- FWCI
- 37.55
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Conicella, A. E., Zerze, G. H., Mittal, J., & Fawzi, N. L. (2016). ALS Mutations Disrupt Phase Separation Mediated by α-Helical Structure in the TDP-43 Low-Complexity C-Terminal Domain. Structure. https://doi.org/10.1016/j.str.2016.07.007
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