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TAR DNA-binding protein 43 AI simulator
(@TAR DNA-binding protein 43_simulator)
Hub AI
TAR DNA-binding protein 43 AI simulator
(@TAR DNA-binding protein 43_simulator)
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.
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.
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. However, further oligomerization brings to more toxic accumulates. This process of polymerization into dimers, larger forms or just stabilizing monomers is dependent on TDP-43 conformational equilibrium between monomers, homodimers and oligomers. Hence, in TDP-43 diseased cells, TDP-43's over-expression leads to the NTD showing high propensity to aggregate. Contrary to this, in normal cells, normal levels of TDP-43 allow for folded NTD, preventing aggregates and polymers formation.
More recently, this domain was found to have a ubiquitin-like structure. It bears 27,6% of homology with Ubiquitin-1 and a β1-β2-α1-β3-β4-β5-β6 + 2*SO42- form. Ubiquitin-like domain are usually associated with a greater affinity for RNA/DNA. However, in the unique case of TDP-43, the Ubiquitin-like NTD binds directly to ssDNA. This interaction permits the conformational equilibrium cited higher to shift towards non-aggregated forms.
The domain spanning from [1,80] has a solenoid-like structure which sterically impedes interactions between aggregation prone C-term regions.
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.
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.
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. However, further oligomerization brings to more toxic accumulates. This process of polymerization into dimers, larger forms or just stabilizing monomers is dependent on TDP-43 conformational equilibrium between monomers, homodimers and oligomers. Hence, in TDP-43 diseased cells, TDP-43's over-expression leads to the NTD showing high propensity to aggregate. Contrary to this, in normal cells, normal levels of TDP-43 allow for folded NTD, preventing aggregates and polymers formation.
More recently, this domain was found to have a ubiquitin-like structure. It bears 27,6% of homology with Ubiquitin-1 and a β1-β2-α1-β3-β4-β5-β6 + 2*SO42- form. Ubiquitin-like domain are usually associated with a greater affinity for RNA/DNA. However, in the unique case of TDP-43, the Ubiquitin-like NTD binds directly to ssDNA. This interaction permits the conformational equilibrium cited higher to shift towards non-aggregated forms.
The domain spanning from [1,80] has a solenoid-like structure which sterically impedes interactions between aggregation prone C-term regions.
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