TAR DNA-binding protein 43
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]
Structure[]
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal domain spanning residues 1-76 (NTD) with a well-defined fold that has been shown to form a dimer or oligomer;[6][7] 2 highly conserved folded RNA recognition motifs spanning residues 106-176 (RRM1) and 191-259 (RRM2), respectively, required to bind target RNA and DNA;[8] an unstructured C-terminal domain encompassing residues 274-414 (CTD), which contains a glycine-rich region, is involved in protein-protein interactions, and harbors most of the mutations associated with familial amyotrophic lateral sclerosis.[9]
The entire protein devoid of large solubilising tags has been purified.[10] The full-length protein is a dimer.[10] The dimer is formed due to a self-interaction between two NTD domains,[6][7] where the dimerisation can be propagated to form higher-order oligomers.[6]
The protein sequence also has a nuclear localization signal (NLS, residues 82–98), a former nuclear export signal (NES residues 239–250) and 3 putative caspase-3 cleavage sites (residues 13, 89, 219).[10]
TDP-43 is a 414 amino acids long, 43 kDa heavy protein. From N-term to C-term one can delimit:
N-Terminal domain (NTD)[]
The NTD located between residues 1 and 76 is involved in TDP-43 polymerization.[11] Indeed, dimers are formed by head-to-head interactions between NTDs, and the polymer thus obtained allows for pre-mRNA splicing.[12] However, further oligomerization brings to more toxic accumulates. This process of polymerization into dimers, larger forms or just stabilizing monomers is dependent on TDP-43 conformational equilibrium between monomers, homodimers and oligomers. Hence, in diseased cells, TDP-43 is overexpressed and this leads to a NTD showing high propensity to aggregate. Contrary to this, in normal cells, normal levels of TDP-43 allow for folded NTD, preventing aggregates and polymers formation.
More recently, this domain was found to have a ubiquitin-like structure. It bears 27,6% of homology with Ubiquitin-1 and a β1-β2-α1-β3-β4-β5-β6 + 2*SO42- form.[13] Ubiquitin-like domain are usually associated with a greater affinity for RNA/DNA. However, in the unique case of TDP-43, the Ubiquitin-like NTD binds directly to ssDNA. This interaction permits the conformational equilibrium cited higher to shift towards non-aggregated forms.[14]
The domain spanning from [1,80] has a solenoid-like structure which sterically gaps aggregation prone C-term region.[12]
All of this raises the possibility that NTD and the RNA Recognition Motifs (later on defined) could cooperatively interact with nucleic acids to accomplish TDP-43’s physiological functions.[15]
Mitochondrial localization signal[]
There are six mitochondrial localization signals[16] to be accounted on TDP-43’s amino acid sequence, although only M1, M3, and M5 were shown to be essential for mitochondial localization. Indeed, their ablation leads to a lessened mitochondrial localization.
These localizing sequences are found on the following amino acids:
M1: [35, 41], M2: [105, 112], M3: [146-150], M4: [228, 235], M5: [294, 300], M6: [228, 236].
Nuclear localization signal (NLS)[]
The nuclear localization signal (NLS) domain is located between residues 82 and 98 is of critical importance in ALS, and such is witnessed by the depletion or the mutations (notably A90V) of this domain, which cause loss-of-function from nucleus and promote aggregating, two processes very likely to conduct to TDP-43’s toxic gain of function.[12]
It is thereby of the utmost importance to note that TDP-43’s nuclear localization is absolutely critical for it to fulfill its physiological functions.[15]
RNA recognition motif[]
The RNA recognition motif ranges between residues 105 and 181, much like many hnRNPs, TDP-43’s RRMs encompass highly conserved motifs of primary importance for fulfilling their function. Both RRMs follow this pattern: β1-α1-β2-β3-α2-β4-β5,[12] which allows them to bind to both RNA and DNA onto UG/TG-repeats of 3’UTR (Untranslated Terminal Regions) end of mRNA/DNA.[11]
These sequences mainly ensure mRNA processing, RNA export and RNA stabilizing. It is notaby thanks to these sequences that TDP-43 importantly binds to its own mRNA regulates its very own solubility and polymerization.
RRM2[]
RRM2 spans between residues 181 and 261. In pathological conditions, it notably binds to p65/NF-kB, an apoptosis implicated factor, and is thus a potential therapeutic target. Moreover it can be burdened with a mutation, D169G, altering a key cleaving site for regulating formation of toxic inclusions.[17]
Nuclear export signal (NES)[]
The nuclear export signal is located between residues 239 and 251 sequence probably bears a role in TDP-43’s shuttling function, and was recently found using a prediction algorithm.[18]
Disordered glycin rich C-terminal domain (CTD)[]
The Disordered Glycin Rich C-terminal domain is located between residues 277 and 414, much like 70 other RNA binding proteins, TDP-43 bears a Q/N rich domain [344, 366] which resembles yeast prion sequence. This sequence is called a Prion-Like Domain (PLD).[19]
PLDs are low complexity sequences that have been reported to mediate gene regulation via Liquid-Liquid Phase Transition (LLP) thus driving RNP granule assembly.[12] Forming these microscopically visible RNP granules is thought to induce more effective gene regulatory process.[20]
It is here noted that LLP are reversible phenomenons of de-mixing a solution into two distinct liquid phases, hereby forming granules.
This CTD is often reported to play important role in pathogenic behavior of TDP-43:
RNPs granules could also have a role in stress response, and thus, aging, or persistance stress could lead the LLPs to turn into irreversible Liquid Solid Phase sepration, pathological aggregates notably found in ALS neurons.[21]
CTD’s disorganized structure can turn into a full fledged Amyloid-like Beta-sheet rich structure causing it to adopt prion-like properties which will be detailed later on.[12]
Moreover, CTFs are a common maker in diseased neurons and are argued to be of high toxicity.
However, notice is to be taken that some points are not always consensual. Indeed, due to its hydrophobic structure, TDP-43 can be hard to analyze, and parts of it remain somewhat vague. Precise sites of phosphorylation, methylation, or even binding are still a bit elusive.[12]
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.[22][23] A similar pseudogene is present on chromosome 20.[24]
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.[25]
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.[26][27]
In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[28] It has also shown to be a in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[29]
It has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[30] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[31]
DNA repair[]
TDP-43 protein is a key element of the non-homologous end joining (NHEJ) enzymatic pathway that repairs DNA double-strand breaks (DSBs) in pluripotent stem cell-derived motor neurons.[32] TDP-43 is rapidly recruited to DSBs where it acts as a scaffold for the further recruitment of the XRCC4-DNA ligase protein complex that then acts to seal the DNA breaks. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic ALS patients’ spinal cord specimens there is significant DSB accumulation and reduced levels of NHEJ.[32]
Clinical significance[]
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[33]) and in amyotrophic lateral sclerosis (ALS).[34][35] Elevated levels of the TDP-43 protein have also been identified in individuals diagnosed with chronic traumatic encephalopathy, and has also been associated with ALS leading to the inference that athletes who have experienced multiple concussions and other types of head injury are at an increased risk for both encephalopathy and motor neuron disease (ALS).[36] Abnormalities of TDP-43 also occur in an important subset of Alzheimer's disease patients, correlating with clinical and neuropathologic features indexes.[37] Misfolded TDP-43 is found in the brains of older adults over age 85 with limbic-predominant age-related TDP-43 encephalopathy, (LATE), a form of dementia. New monoclonal antibodies, 2G11 and 2H1, have been developed to specify different TDP-43 inclusion types that occur across neurodegenerative diseases, without relying on hyper-phosphorylated epitopes.[38] These antibodies were raised against an epitope within the RRM2 domain (amino acid residues 198–216).[38]
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).[39] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[40][41][42] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[43] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[44] A recent study has demonstrated that cellular stress can trigger the abnormal cytoplasmic mislocalisation of TDP-43 in spinal motor neurons in vivo, providing insight into how TDP-43 pathology may develop in sporadic ALS patients.[45]
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Further reading[]
- 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. S2CID 20773388.
- Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Tokai N, Fujimoto-Nishiyama A, Toyoshima Y, Yonemura S, Tsukita S, Inoue J, Yamamota T (February 1996). "Kid, a novel kinesin-like DNA binding protein, is localized to chromosomes and the mitotic spindle". The EMBO Journal. 15 (3): 457–467. doi:10.1002/j.1460-2075.1996.tb00378.x. PMC 449964. PMID 8599929.
- Bonaldo MF, Lennon G, Soares MB (September 1996). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Research. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, et al. (March 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–435. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Buratti E, Dörk T, Zuccato E, Pagani F, Romano M, Baralle FE (April 2001). "Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping". The EMBO Journal. 20 (7): 1774–1784. doi:10.1093/emboj/20.7.1774. PMC 145463. PMID 11285240.
- Buratti E, Baralle FE (September 2001). "Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9". The Journal of Biological Chemistry. 276 (39): 36337–36343. doi:10.1074/jbc.M104236200. PMID 11470789.
- Wang IF, Reddy NM, Shen CK (October 2002). "Higher order arrangement of the eukaryotic nuclear bodies". Proceedings of the National Academy of Sciences of the United States of America. 99 (21): 13583–13588. Bibcode:2002PNAS...9913583W. doi:10.1073/pnas.212483099. PMC 129717. PMID 12361981.
- Lehner B, Sanderson CM (July 2004). "A protein interaction framework for human mRNA degradation". Genome Research. 14 (7): 1315–1323. doi:10.1101/gr.2122004. PMC 442147. PMID 15231747.
- Wiemann S, Arlt D, Huber W, Wellenreuther R, Schleeger S, Mehrle A, et al. (October 2004). "From ORFeome to biology: a functional genomics pipeline". Genome Research. 14 (10B): 2136–2144. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE (November 2005). "TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing". The Journal of Biological Chemistry. 280 (45): 37572–37584. doi:10.1074/jbc.M505557200. PMID 16157593.
- Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, et al. (September 2005). "A human protein-protein interaction network: a resource for annotating the proteome". Cell. 122 (6): 957–968. doi:10.1016/j.cell.2005.08.029. hdl:11858/00-001M-0000-0010-8592-0. PMID 16169070. S2CID 8235923.
- Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
- Mehrle A, Rosenfelder H, Schupp I, del Val C, Arlt D, Hahne F, et al. (January 2006). "The LIFEdb database in 2006". Nucleic Acids Research. 34 (Database issue): D415–D418. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
External links[]
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Wikimedia Commons has media related to TAR DNA-binding protein 43, TDP-43. |
- GeneReviews/NCBI/NIH/UW entry on TARDBP-Related Amyotrophic Lateral Sclerosis
- Overview of all the structural information available in the PDB for UniProt: Q13148 (TAR DNA-binding protein 43) at the PDBe-KB.
- Genes on human chromosome 1
- DNA-binding proteins