TARDBP

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TARDBP
Protein TARDBP PDB 1wf0.png
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTARDBP, ALS10, TDP-43, TAR DNA binding protein
External IDsMGI: 2387629 HomoloGene: 7221 GeneCards: TARDBP
Gene location (Human)
Chromosome 1 (human)
Chr.Chromosome 1 (human)[1]
Chromosome 1 (human)
Genomic location for TARDBP
Genomic location for TARDBP
Band1p36.22Start11,012,344 bp[1]
End11,026,420 bp[1]
RNA expression pattern
PBB GE TARDBP 221264 s at fs.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_007375

RefSeq (protein)

NP_031401
NP_031401.1

Location (UCSC)Chr 1: 11.01 – 11.03 MbChr 4: 148.61 – 148.63 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a protein that in humans is encoded by the TARDBP gene.[5]

Function[edit]

TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene.[6] A similar pseudogene is present on chromosome 20.[7]

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons.[8]

TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[5] It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene.

In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[9] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[10]

Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[11] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[12]

Clinical significance[edit]

A hyper-phosphorylated, ubiquitinated and cleaved form of TDP-43—known as pathologic TDP43—is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-TDP, previously referred to as FTLD-U[13]) and in amyotrophic lateral sclerosis (ALS).[14][15] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, a condition that often mimics ALS and that has been associated with athletes who have experienced multiple concussions and other types of head injury.[16] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[17]

HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNA genome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator "Tat" is dependent on an RNA regulatory element (TAR) located "downstream" (i.e. to-be transcribed at a later point in time) of the transcription initiation site.

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[18] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[19][20] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[21] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[22]

References[edit]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000120948 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041459 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". 
  4. ^ "Mouse PubMed Reference:". 
  5. ^ a b Ou SH, Wu F, Harrich D, García-Martínez LF, Gaynor RB (June 1995). "Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs". Journal of Virology. 69 (6): 3584–96. PMC 189073Freely accessible. PMID 7745706. 
  6. ^ Kuo PH, Doudeva LG, Wang YT, Shen CK, Yuan HS (April 2009). "Structural insights into TDP-43 in nucleic-acid binding and domain interactions". Nucleic Acids Research. 37 (6): 1799–808. doi:10.1093/nar/gkp013. PMC 2665213Freely accessible. PMID 19174564. 
  7. ^ Gene Result
  8. ^ Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G (January 2011). "Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes". The Journal of Biological Chemistry. 286 (2): 1204–15. doi:10.1074/jbc.M110.190884. PMC 3020728Freely accessible. PMID 21051541. 
  9. ^ Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (June 2007). "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neurosciences. 35 (2): 320–7. doi:10.1016/j.mcn.2007.03.007. PMID 17481916. 
  10. ^ Wang IF, Wu LS, Chang HY, Shen CK (May 2008). "TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor". Journal of Neurochemistry. 105 (3): 797–806. doi:10.1111/j.1471-4159.2007.05190.x. PMID 18088371. 
  11. ^ Caragounis A, Price KA, Soon CP, Filiz G, Masters CL, Li QX, Crouch PJ, White AR (May 2010). "Zinc induces depletion and aggregation of endogenous TDP-43". Free Radical Biology & Medicine. 48 (9): 1152–61. doi:10.1016/j.freeradbiomed.2010.01.035. PMID 20138212. 
  12. ^ Garnier C, Devred F, Byrne D, Puppo R, Roman AY, Malesinski S, Golovin AV, Lebrun R, Ninkina NN, Tsvetkov PO (July 2017). "Zinc binding to RNA recognition motif of TDP-43 induces the formation of amyloid-like aggregates". Scientific Reports. 7 (1): 6812. doi:10.1038/s41598-017-07215-7. PMID 28754988. 
  13. ^ Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (July 2011). "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathologica. 122 (1): 111–3. doi:10.1007/s00401-011-0845-8. PMC 3285143Freely accessible. PMID 21644037. 
  14. ^ Bräuer S, Zimyanin V, Hermann A (April 2018). "Prion-like properties of disease-relevant proteins in amyotrophic lateral sclerosis". Journal of Neural Transmission. 125 (4): 591–613. doi:10.1007/s00702-018-1851-y. PMID 29417336. 
  15. ^ Lau DH, Hartopp N, Welsh NJ, Mueller S, Glennon EB, Mórotz GM, Annibali A, Gomez-Suaga P, Stoica R, Paillusson S, Miller CC (February 2018). "Disruption of ER-mitochondria signalling in fronto-temporal dementia and related amyotrophic lateral sclerosis". Cell Death & Disease. 9 (3): 327. doi:10.1038/s41419-017-0022-7. PMC 5832427Freely accessible. PMID 29491392. 
  16. ^ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times, August 18, 2010. Accessed August 18, 2010.
  17. ^ Tremblay C, St-Amour I, Schneider J, Bennett DA, Calon F (September 2011). "Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease". Journal of Neuropathology and Experimental Neurology. 70 (9): 788–98. doi:10.1097/nen.0b013e31822c62cf. PMC 3197017Freely accessible. PMID 21865887. 
  18. ^ Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (July 2007). "TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease". Acta Neuropathologica. 114 (1): 63–70. doi:10.1007/s00401-007-0226-5. PMID 17492294. 
  19. ^ Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (March 2008). "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis". Science. 319 (5870): 1668–72. doi:10.1126/science.1154584. PMID 18309045. 
  20. ^ Gendron TF, Rademakers R, Petrucelli L (2013). "TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43". Journal of Alzheimer's Disease. 33 Suppl 1 (suppl 1): S35–45. doi:10.3233/JAD-2012-129036. PMC 3532959Freely accessible. PMID 22751173. 
  21. ^ Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (March 2013). "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature. 495 (7442): 467–73. doi:10.1038/nature11922. PMC 3756911Freely accessible. PMID 23455423. 
  22. ^ .Mompeán M, Romano V, Pantoja-Uceda D, Stuani C, Baralle FE, Buratti E, Laurents DV (April 2016). "The TDP-43 N-terminal domain structure at high resolution". The FEBS Journal. 283 (7): 1242–60. doi:10.1111/febs.13651. PMID 26756435. 

Further reading[edit]

External links[edit]