The DOI matches its Crossref record; 86 of the 86 references it cites were found in a registry or an index.
TDP-43 α-helical structure tunes liquid–liquid phase separation and function
Open accessAbstract
Liquid–liquid phase separation (LLPS) is involved in the formation of membraneless organelles (MLOs) associated with RNA processing. The RNA-binding protein TDP-43 is present in several MLOs, undergoes LLPS, and has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS). While some ALS-associated mutations in TDP-43 disrupt self-interaction and function, here we show that designed single mutations can enhance TDP-43 assembly and function via modulating helical structure. Using molecular simulation and NMR spectroscopy, we observe large structural changes upon dimerization of TDP-43. Two conserved glycine residues (G335 and G338) are potent inhibitors of helical extension and helix–helix interaction, which are removed in part by variants at these positions, including the ALS-associated G335D. Substitution to helix-enhancing alanine at either of these positions dramatically enhances phase separation in vitro and decreases fluidity of phase-separated TDP-43 reporter compartments in cells. Furthermore, G335A increases TDP-43 splicing function in a minigene assay. Therefore, the TDP-43 helical region serves as a short but uniquely tunable module where application of biophysical principles can precisely control assembly and function in cellular and synthetic biology applications of LLPS.
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Cited by
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Systematic identification of conditionally folded intrinsically disordered regions by AlphaFold2
Alderson, T. R., Pritišanac, I., Kolarić, Đ., Moses, A. M., & Forman-Kay, J. D. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2304302120 · Cited by 240
Metadata
- Authors
- Conicella, A. E., Dignon, G. L., Zerze, G. H., Schmidt, H. B., D’Ordine, A. M., Kim, Y. C., Rohatgi, R., Ayala, Y. M., Mittal, J., & Fawzi, N. L.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2020-03-04
- Volume
- 117
- Issue
- 11
- Pages
- 5883-5894
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W3009501790
- Cited by
- 375
- References
- 86
- FWCI
- 19.85
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Conicella, A. E., Dignon, G. L., Zerze, G. H., Schmidt, H. B., D’Ordine, A. M., Kim, Y. C., Rohatgi, R., Ayala, Y. M., Mittal, J., & Fawzi, N. L. (2020). TDP-43 α-helical structure tunes liquid–liquid phase separation and function. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1912055117
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