motifs/domains
| N-terminal QGSY-rich region, and contains an independently |
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folded structural domain (NTD), promoting TARDBP oligomerization in a concentration-dependent manner  |
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two highly conserved RNA recognition motifs (RRM1 and RRM2) flanked by the N-terminal and the C-terminal tail |
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a nuclear localization signal (NLS) |
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a nuclear export signal (NES) |
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potential acetylation, sumoylation and phosphorylation sites |
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three caspases-3 cleavage sites |
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a hydrophobic patch (AAs 318-343) as the amyloidogenic core essential for TARDBP aggregation |
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two RNA binding domains (RBD) |
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multiple RGG repeats, which are extensively dimethylated at arginine residues (138) |
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C-terminal tail containing a glycine-rich region often found to mediate protein–protein interactions (Zhang 2009), and a zinc finger motif (C-terminal fragments were excluded from TARDBP RNP complexes but retained interaction with FUS/TLS, suggesting that the accumulation of such fragments may compromise TARDBP-FUS/TLS complex function) , and required for self-regulation |
SUBCELLULAR LOCALIZATION
| intracellular
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| intracellular,cytoplasm,cytosolic,granule
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| intracellular,nucleus,nucleoplasm,nuclear bodies,coiled bodies (Cajal)
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| text
| in control motor neurons, TDP43 is almost exclusively nuclear, whereas in ALS spinal motor neurons, TDP43 is predominantly localized to the cytosol |
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normally, a nuclear protein but neurons with cytoplasmic inclusions have a substantial loss of nuclear TARDBP, suggesting it redistributes to the cytoplasm (Zhang 2009) |
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also present in the cytosol where they are involved in diverse aspects of RNA metabolism, regulating the spatiotemporal fate of mRNA, i.e. subcellular localization, translation or degradation (Lagier-tourenne 2010) |
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in healthy cells, TARDBP is mainly localized to the nucleus, and in the majority of ALS cases, is depleted from the nucleus of motor neurons, and hyperphosphorylated and ubiquitinated TARDBP C-terminal fragments (CTFs) accumulate in insoluble cytoplasmic aggregates |
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predominantly located in the nucleus as a dimer |
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cytosolic accumulation of TARDBP may be a coping mechanism to alleviate or temporarily delay the effects of TARDBP on aberrant mRNA |
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associates with nuclear bodies including Gemini of coiled bodies (GEMs) |
| basic FUNCTION
| transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription |
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regulating alternate splicing of the CFTR and apoA-II genes |
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capable of binding DNA and RNA, which regulates transcription and splicing but may also be involved in microRNA biogenesis, apoptosis and cell division |
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regulates retinoblastoma protein phosphorylation through the repression of cyclin-dependent kinase 6 (CDK6)expression |
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major protein present in the hallmark inclusion bodies of frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), suggesting a role for transcriptional dysregulation in FTLD-U pathophysiology |
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could act as a transcriptional repressor, translational repressor as well as a splicing factor promoting the exon 9 exclusion of the CFTR pre-mRNA and could promote the inclusion of exon 7 during splicing of the SMN2 pre-mRNA |
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multifunctional RNA-binding protein for a diverse set of cellular activities |
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heterogeneous nuclear ribonucleoprotein that functions in RNA transcription and pre-mRNA splicing |
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might be involved in the transport of mRNAs to synaptic sites, where active translation of the transported mRNAs occurs |
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functions in regulating transcription and alternative splicing |
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unique NEFL mRNA-binding protein that is altered in its somatotopic localization in ALS spinal motor neurons and potentially contributes to the formation of NF aggregates in ALS |
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may regulates the activities of Rho family members through protein geranylgeranylation |
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DNA/RNA-binding protein implicated in multiple steps of transcriptional and post-transcriptional regulation of gene expression |
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with FUS may play roles in micro-RNA (miRNA) processing |
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TARDBP and FUS implicated in neurodegeneration through errors in multiple steps of RNA processing |
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critical for fat metabolism and embryonic stem cell survival |
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physiological role for TARDBP in regulating body fat and regulate TBC1D1 a gene associated with human obesity) |
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critical role in controlling the formation of SMN-associated GEMs (Gemini of coiled bodies) that may impact on RNA metabolism in motor neurons |
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roles in regulation of RNA splicing and RNA transcription of a subset of genes, including those members of the neurofilament family |
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crucial for the maintenance of neuronal physiology, including that of motor neurons |
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direct role for its aggregation in ALS pathogenesis |
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with FUS/TLS operate together in a common biochemical pathway |
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regulates expression of HDAC6, which plays key roles in autophagic clearance of protein aggregates and is linked to suppression of neurodegeneration |
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its cellular levels are under tight control and it is likely that disease-associated TARDBP aggregates disrupt its self-regulation, thus contributing to pathogenesis |
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RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation |
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TARDBP -induced death is associated with the increase of BCL2L11 expression and the decrease of BCL2L1 expression |
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facilitates the production of a subset of precursor miRNAs and promotes the processing of these pre-miRNAs via binding to their terminal loops |
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involved in miRNA biogenesis that is indispensable for neuronal outgrowth |
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potential role in the regulation of axonal growth, suggesting that impairment in the post-transcriptional regulation of mRNAs in the cytoplasm of motor neurons may be a major factor in the development of ALS |
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potential functional role in the regulation of mRNA fate in motor neuron axons |
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associates with stalled ribosomes and contributes to cell survival during cellular stress |
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contributes to Gemini of coiled bodies formation and the biogenesis of U snRNAs, particularly U12 snRNA, in tissues affected by ALS |
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nuclear TARDBP contributes to the autoregulation, suggesting that the absence of nuclear TARDBP induces an abnormal autoregulation and increases the amount of TARDBP mRNA |
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TARDBP proteinopathies induce impairment in the ubiquitin proteasome system (UPS), as evidenced by an accumulation of ubiquitinated proteins and a reduction in proteasome activity in neuronal cells |
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intranuclear protein involved in RNA splicing, trafficking, stabilization, and thus, the regulation of gene expression |
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