TAR DNA-binding protein 43 (TARDBP)
The protein contains 414 amino acids for an estimated molecular weight of 44740 Da.
RNA-binding protein that is involved in various steps of RNA biogenesis and processing (PubMed:23519609). Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs (PubMed:23519609, PubMed:24240615, PubMed:24464995). In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases (PubMed:21358640, PubMed:29438978). Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts (PubMed:28794432). Regulates also mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening (PubMed:30520513). In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival (PubMed:23398327, PubMed:19765185). Participates also in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins (PubMed:30464263). Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner (PubMed:27123980). Negatively regulates the expression of CDK6 (PubMed:19760257). Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-de (updated: Oct. 7, 2020)
Protein identification was indicated in the following studies:
- Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
- Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
- Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
- Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
- D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
- Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.
Methods
The following articles were analysed to gather the proteome content of erythrocytes.
The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.
| Publication | Identification 1 | Uniprot mapping 2 | Not mapped / Obsolete | TrEMBL | Swiss-Prot |
|---|---|---|---|---|---|
| Goodman (2013) | 2289 (gene list) | 2278 | 53 | 20599 | 2269 |
| Lange (2014) | 1234 | 1234 | 7 | 28 | 1224 |
| Hegedus (2015) | 2638 | 2622 | 0 | 235 | 2387 |
| Wilson (2016) | 1658 | 1528 | 170 | 291 | 1068 |
| d'Alessandro (2017) | 1826 | 1817 | 2 | 0 | 1815 |
| Bryk (2017) | 2090 | 2060 | 10 | 108 | 1942 |
| Chu (2018) | 1853 | 1804 | 55 | 362 | 1387 |
1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry
The compilation of older studies can be retrieved from the Red Blood Cell Collection database.
The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.
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Biological Process
3'-UTR-mediated mRNA destabilization
3'-UTR-mediated mRNA stabilization
MRNA processing
Negative regulation by host of viral transcription
Negative regulation of gene expression
Negative regulation of protein phosphorylation
Nuclear inner membrane organization
Positive regulation of insulin secretion
Positive regulation of protein import into nucleus
Regulation of apoptotic process
Regulation of cell cycle
Regulation of circadian rhythm
Regulation of gene expression
Regulation of protein stability
Regulation of RNA metabolic process
Response to endoplasmic reticulum stress
Rhythmic process
RNA splicing
Transcription by RNA polymerase II
Cellular Component
Cytoplasm
Cytoplasmic stress granule
Interchromatin granule
Nuclear speck
Nucleoplasm
Nucleus
Perichromatin fibrils
Ribonucleoprotein complex
Molecular Function
DNA-binding transcription factor activity
Double-stranded DNA binding
Identical protein binding
MRNA 3'-UTR binding
Nucleotide binding
Poly(A) RNA binding
Pre-mRNA intronic binding
RNA binding
RNA polymerase II cis-regulatory region sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
Sequence-specific DNA binding
Sequence-specific double-stranded DNA binding
Single-stranded RNA binding
Transcriptional activator activity, RNA polymerase II distal enhancer sequence-specific DNA binding
The reference OMIM entry for this protein is 605078
Tar dna-binding protein; tardbp
Tar dna-binding protein, 43-kd; tdp43
DESCRIPTION
The TARDBP gene encodes the 43-kD TAR DNA-binding protein, which was originally identified as a transcriptional repressor that binds to TAR DNA of human immunodeficiency virus type 1. It is also involved in regulation of gene expression and splicing (summary by Benajiba et al., 2009).CLONING
HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. The HIV Tat protein (see 601409), a transcription-activating protein that binds to the bulge region of a stable stem-bulge-loop structure, TAR RNA, activates the HIV-1 long terminal repeat (LTR). Tat activates the LTR less efficiently in rodent than in human cells, suggesting that cellular RNA-binding proteins are also involved in the regulation of HIV replication. TAR DNA may possess distinct regulatory elements that play a role in modulating HIV-1 gene expression. To characterize cellular factors that bind to TAR DNA, Ou et al. (1995) screened a HeLa cell cDNA library using a TAR DNA probe and identified a cDNA encoding a 43-kD TAR DNA-binding protein, TARDBP, which they called TDP43. The deduced 414-amino acid TARDBP contains a ribonucleoprotein (RNP)-binding domain and a glycine-rich region. Northern blot analysis detected a ubiquitously expressed, 2.8-kb TARDBP transcript. SDS-PAGE analysis showed that recombinant and native TARDBP are expressed as 43-kD proteins. By database analysis and cDNA cloning, Wang et al. (2004) determined that the TARDBP gene generates at least 11 mRNA species by alternative splicing. The shorter transcripts encode proteins lacking the glycine-rich domain, which is required for the exon-skipping activity of TARDBP. Benajiba et al. (2009) stated that TDP43 contains 2 RNA recognition motifs, a nuclear export domain, and a C-terminal domain that is essential for binding to heterogeneous nuclear ribonucleoproteins (hnRNPs) and for splicing inhibition. TDP43 is normally localized in the nucleus, but in pathologic conditions, the cleaved form of TDP43 is mainly present in the cytoplasmGENE STRUCTURE
Wang et al. (2004) determined that the TARDBP gene contains 6 exons.MAPPING
By genomic sequence analysis, Wang et al. (2004) mapped the TARDBP gene to chromosome 1p36.21. They also identified intronless TARDBP-like pseudogenes on chromosomes 2, 6, 8, 13, and 20 that likely originated from retrotransposition events. Wang et al. (2004) mapped the mouse Tardbp gene to chromosome 4E2 in a region that shows homology of synteny to human chromosome 1p36.GENE FUNCTION
Functional analysis by Ou et al. (1995) indicated that TARDBP does not bind RNA. Gel retardation analysis followed by Western blot analysis (Shift-Western analysis) demonstrated that the RNP-binding motifs of TARDBP bind to the pyrimidine-rich motifs of TAR DNA. In an in vitro transcription analysis, increasing amounts of TARDBP, in the presence or absence of Tat, decreased the level of transcription from the HIV-1 LTR but not from the adenovirus major late promoter. Using reporter plasmids, Wang et al. (2004) determined that deletion of the glycine-rich domain of mouse Tardbp resulted in loss of about 90% of its ability to activate exon skipping in the CFTR gene (602421). RNA splicing mutations in the CFTR gene are thought to lead to dysfunction of several organs such as lung, sweat glands, genital tract, intestine and pancreas, produ ... More on the omim web site
Oct. 20, 2020: Protein entry updated
Automatic update: Entry updated from uniprot information.
May 11, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 22, 2019: Protein entry updated
Automatic update: Entry updated from uniprot information.
Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated
Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated
March 16, 2016: Protein entry updated
Automatic update: OMIM entry 605078 was added.
Jan. 25, 2016: Protein entry updated
Automatic update: model status changed