TAR DNA-binding protein 43

Transactive response DNA binding protein 43 kDa (TAR DNA-binding protein 43 or TDP-43) is a protein that in humans is encoded by the TARDBP gene.

Structure

TDP-43 is 414 amino acid residues long. It consists of four domains: an N-terminal domain spanning residues 1–76 (NTD) with a well-defined fold that has been shown to form a dimer or oligomer; two highly conserved folded RNA recognition motifs spanning residues 106–176 (RRM1) and 191–259 (RRM2), respectively, required to bind target RNA and DNA; an unstructured C-terminal domain encompassing residues 274–414 (CTD), which contains a glycine-rich region, is involved in protein-protein interactions, and harbors most of the mutations associated with familial amyotrophic lateral sclerosis.

The entire protein devoid of large solubilising tags has been purified. The full-length protein is a dimer. The dimer is formed due to a self-interaction between two NTD domains, where the dimerisation can be propagated to form higher-order oligomers.

The protein sequence also has a nuclear localization signal (NLS, residues 82–98), a former nuclear export signal (NES residues 239–250) and 3 putative caspase-3 cleavage sites (residues 13, 89, 219).

In December 2021 the structure of TDP-43 was resolved with cryo-EM but shortly after it was argued that in the context of FTLD-TDP the protein involved could be TMEM106B (which has been also resolved with cryo-EM), rather than of TDP-43.

N-Terminal domain (NTD)

The NTD located between residues 1 and 76 is involved in TDP-43 polymerization. Indeed, dimers are formed by head-to-head interactions between NTDs, and the polymer thus obtained allows for pre-mRNA splicing.