We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Different Intermolecular Interactions Drive Nonpathogenic Liquid–Liquid Phase Separation and Potentially Pathogenic Fibril Formation by TDP-43.
- Authors
Zeng, Yu-Teng; Bi, Lu-Lu; Zhuo, Xiao-Feng; Yang, Ling-Yun; Sun, Bo; Lu, Jun-Xia
- Abstract
The liquid–liquid phase separation (LLPS) of proteins has been found ubiquitously in eukaryotic cells, and is critical in the control of many biological processes by forming a temporary condensed phase with different bimolecular components. TDP-43 is recruited to stress granules in cells and is the main component of TDP-43 granules and proteinaceous amyloid inclusions in patients with amyotrophic lateral sclerosis (ALS). TDP-43 low complexity domain (LCD) is able to de-mix in solution, forming the protein condensed droplets, and amyloid aggregates would form from the droplets after incubation. The molecular interactions regulating TDP-43 LCD LLPS were investigated at the protein fusion equilibrium stage, when the droplets stopped growing after incubation. We found the molecules in the droplet were still liquid-like, but with enhanced intermolecular helix–helix interactions. The protein would only start to aggregate after a lag time and aggregate slower than at the condition when the protein does not phase separately into the droplets, or the molecules have a reduced intermolecular helix–helix interaction. In the protein condensed droplets, a structural transition intermediate toward protein aggregation was discovered involving a decrease in the intermolecular helix–helix interaction and a reduction in the helicity. Our results therefore indicate that different intermolecular interactions drive LLPS and fibril formation. The discovery that TDP-43 LCD aggregation was faster through the pathway without the first protein phase separation supports that LLPS and the intermolecular helical interaction could help maintain the stability of TDP-43 LCD.
- Subjects
PHASE separation; MOLECULAR interactions; AMYOTROPHIC lateral sclerosis; CHIMERIC proteins; PROTEIN fractionation
- Publication
International Journal of Molecular Sciences, 2022, Vol 23, Issue 23, p15227
- ISSN
1661-6596
- Publication type
Article
- DOI
10.3390/ijms232315227