TARDBP

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TAR DNA binding protein
Protein TARDBP PDB 1wf0.png
2nd RRM motif of TDP-43. PDB rendering based on 1wf0.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols TARDBP ; ALS10; TDP-43
External IDs OMIM605078 MGI2387629 HomoloGene7221 GeneCards: TARDBP Gene
RNA expression pattern
PBB GE TARDBP 221264 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 23435 230908
Ensembl ENSG00000120948 ENSMUSG00000041459
UniProt Q13148 Q921F2
RefSeq (mRNA) NM_007375 NM_001003898
RefSeq (protein) NP_031401 NP_001003898
Location (UCSC) Chr 1:
11.07 – 11.09 Mb
Chr 4:
148.61 – 148.63 Mb
PubMed search [1] [2]

TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa), is a cellular protein which in humans is encoded by the TARDBP gene.[1]

Discovery[edit]

TARDBP was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[1] It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene. Later it was discovered that hyper-phosphorylated, ubiquitinated and cleaved form of TARDBP, known as pathologic TDP43, is the major disease protein in ubiquitin-positive, tau-, and alpha-synuclein-negative frontotemporal dementia (FTLD-U now referred to as FTLD-TDP) and in Amyotrophic lateral sclerosis (ALS).[2] 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.[3]

Clinical significance[edit]

TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation.

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 of the transcription initiation site. The protein encoded by this gene 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.[4] A similar pseudogene is present on chromosome 20.[5] In spinal motor neurons TDP-43 has also been shown to be a human low molecular weight microfilament (hNFL) mRNA-binding protein.[6] 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.[7]

Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[8] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[9][10] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[11]

References[edit]

  1. ^ a b Ou, SH; Wu, F; Harrich, D; García-Martínez, LF; Gaynor, RB (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 189073. PMID 7745706. 
  2. ^ Neumann, M.; Sampathu, D. M.; Kwong, L. K.; Truax, A. C.; Micsenyi, M. C.; Chou, T. T.; Bruce, J.; Schuck, T.; Grossman, M. et al. (2006). "Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis". Science 314 (5796): 130–3. doi:10.1126/science.1134108. PMID 17023659. 
  3. ^ Schwarz, Alan. "Study Says Brain Trauma Can Mimic A.L.S.", The New York Times, August 18, 2010. Accessed August 18, 2010.
  4. ^ Kuo, P.-H.; Doudeva, L. G.; Wang, Y.-T.; Shen, C.-K. J.; Yuan, H. S. (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 2665213. PMID 19174564. 
  5. ^ Gene Result
  6. ^ Strong, Michael J.; Volkening, Kathryn; Hammond, Robert; Yang, Wencheng; Strong, Wendy; Leystra-Lantz, Cheryl; Shoesmith, Christen (2007). "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neuroscience 35 (2): 320–7. doi:10.1016/j.mcn.2007.03.007. PMID 17481916. 
  7. ^ Wang, I.-Fan; Wu, Lien-Szn; Chang, Hsiang-Yu; Shen, C.-K. James (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. 
  8. ^ Kwong, Linda K.; Neumann, Manuela; Sampathu, Deepak M.; Lee, Virginia M.-Y.; Trojanowski, John Q. (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. 
  9. ^ Sreedharan, J.; Blair, I. P.; Tripathi, V. B.; Hu, X.; Vance, C.; Rogelj, B.; Ackerley, S.; Durnall, J. C. et al. (2008). "TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis". Science 319 (5870): 1668–72. doi:10.1126/science.1154584. PMID 18309045. 
  10. ^ 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): S35–S45. PMC 3532959. PMID 22751173. 
  11. ^ Kim HJ, Kim NC, Wang M, Moore J, Diaz Z, Scarborough EA, Maclea K, Freibaum B, Molliex A, Kanagaraj A, Li S, Pinkus JL, Greenberg SA, Trojanowski J, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Wojtas AM, Boylan KB, Rademakers R, Kottlors M, Kirschner J, Li YR, Gitler AD, Benatar M, King OD, Kimonis V, Ross ED, Weihl CC, Shorter J, and Taylor JP. Mutations in the prion-like domains of hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 2013 Mar 28;495(7442):467-73.

External links[edit]

Further reading[edit]