The TDP-43 N-terminal domain structure at high resolution

Area of Science:

• Neuroscience
• Structural Biology
• Biochemistry

Background:

• Transactive response DNA-binding protein 43 kDa (TDP-43) aggregates are implicated in neurodegenerative diseases.
• The N-terminal domain of TDP-43 (residues 1-77) is essential for recruiting TDP-43 monomers into aggregates.
• Understanding the N-terminal domain's structure is key to understanding TDP-43's role in disease.

Purpose of the Study:

• To determine the complete NMR assignments and three-dimensional structure of the TDP-43 N-terminal domain.
• To characterize the structural features, stability, and dynamics of the TDP-43 N-terminal domain.

Main Methods:

• Nuclear Magnetic Resonance (NMR) spectroscopy was used to obtain (1)H, (15)N, and (13)C assignments.
• Structural restraints included hydrogen bonds, torsion angles, and Nuclear Overhauser Effect (NOE) data.
• Model-free analysis of relaxation rates was employed to assess domain dynamics.

Main Results:

• The complete NMR assignments and structure of the TDP-43 N-terminal domain (residues 1-77) were determined.
• The structure comprises an α-helix and six β-strands, with a unique β-hairpin formation.
• The domain exhibits conformational stability comparable to ubiquitin and possesses a defined hydrophobic core.

Conclusions:

• The determined structure provides the first atomic-level view of the TDP-43 N-terminal domain.
• The structural and stability data offer crucial insights into TDP-43's aggregation mechanism.
• This work lays the foundation for future studies on TDP-43 in neurodegeneration.