TARDBP

TAR DNA binding protein
2nd RRM motif of TDP-43. PDB rendering based on 1wf0.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1WF0​, 2CQG​, 4BS2​, 4IUF​, 2N4P​
Identifiers
Symbols	TARDBP ; ALS10; TDP-43
External IDs	OMIM: 605078 MGI: 2387629 HomoloGene: 7221 GeneCards: TARDBP Gene
Gene ontology Molecular function • nucleotide binding • transcriptional activator activity, RNA polymerase II distal enhancer sequence-specific binding • double-stranded DNA binding • transcription factor activity, sequence-specific DNA binding • RNA binding • mRNA 3'-UTR binding • protein binding • identical protein binding • poly(A) RNA binding Cellular component • nucleus • nucleoplasm • perichromatin fibrils • cytoplasm • nuclear speck • interchromatin granule Biological process • negative regulation of protein phosphorylation • transcription from RNA polymerase II promoter • mRNA processing • RNA splicing • negative regulation of gene expression • nuclear fragmentation involved in apoptotic nuclear change • positive regulation of insulin secretion • response to endoplasmic reticulum stress • negative regulation by host of viral transcription • positive regulation of transcription from RNA polymerase II promoter • regulation of cell cycle • 3'-UTR-mediated mRNA stabilization • nuclear inner membrane organization Sources: Amigo / QuickGO
RNA expression pattern
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: 11.01 – 11.03 Mb	Chr 4: 148.61 – 148.63 Mb
PubMed search

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.^[1]

Function

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.^[2] A similar pseudogene is present on chromosome 20.^[3]

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.^[4]

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.^[1] 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 microfilament (hNFL) mRNA-binding protein.^[5] 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.^[6]

Clinical significance

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^[7]) and in Amyotrophic lateral sclerosis (ALS).^[8] 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.^[9] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.^[10]

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).^[11] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.^[12][13] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.^[14] The N-terminal domain, which contributes importantely to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops ^[15].

References

Further reading

External links

Wikimedia Commons has media related to TAR DNA-binding protein 43, TDP-43.

• GeneReviews/NCBI/NIH/UW entry on TARDBP-Related Amyotrophic Lateral Sclerosis

PDB gallery 1wf0: Solution structure of RRM domain in TAR DNA-binding protein-43  2cqg: Solution structure of the RNA binding domain of TAR DNA-binding protein-43