The cooperative binding of TDP-43 to GU-rich RNA repeats antagonizes TDP-43 aggregation
TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRN...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | article |
| Language: | EN |
| Published: |
eLife Sciences Publications Ltd
2021
|
| Subjects: | |
| Online Access: | https://doaj.org/article/de0ec8831ecd4f1da1a28a35d038e526 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | TDP-43 is a nuclear RNA-binding protein that forms neuronal cytoplasmic inclusions in two major neurodegenerative diseases, ALS and FTLD. While the self-assembly of TDP-43 by its structured N-terminal and intrinsically disordered C-terminal domains has been widely studied, the mechanism by which mRNA preserves TDP-43 solubility in the nucleus has not been addressed. Here, we demonstrate that tandem RNA recognition motifs of TDP-43 bind to long GU-repeats in a cooperative manner through intermolecular interactions. Moreover, using mutants whose cooperativity is impaired, we found that the cooperative binding of TDP-43 to mRNA may be critical to maintain the solubility of TDP-43 in the nucleus and the miscibility of TDP-43 in cytoplasmic stress granules. We anticipate that the knowledge of a higher order assembly of TDP-43 on mRNA may clarify its role in intron processing and provide a means of interfering with the cytoplasmic aggregation of TDP-43. |
|---|