biology

TAR DNA-binding protein 43

TAR DNA-binding protein 43 is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand TAR DNA-binding protein 43 rather than just read about it. In short: Transactive response DNA binding protein 43 kDa (TAR DNA-binding protein 43 or TDP-43) is a protein that in humans is encoded by the TARDBP gene. Structure TDP-43 is 414 amino acid residues long.

Key takeaways

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Reference excerpt

Transactive response DNA binding protein 43 kDa (TAR DNA-binding protein 43 or TDP-43) is a protein that in humans is encoded by the TARDBP gene.

Structure TDP-43 is 414 amino acid residues long. It consists of four 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; two highly conserved folded RNA recognition motifs spanning residues 106–176 (RRM1) and 191–259 (RRM2), respectively, required to bind target RNA and DNA; 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. The entire protein devoid of large solubilising tags has been purified. The full-length protein is a dimer. The dimer is formed due to a self-interaction between two NTD domains, where the dimerisation can be propagated to form higher-order oligomers. 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). In December 2021 the structure of TDP-43 was resolved with cryo-EM but shortly after it was argued that in the context of FTLD-TDP the protein involved could be TMEM106B (which has been also resolved with cryo-EM), rather than of TDP-43.

N-Terminal domain (NTD) The NTD located between residues 1 and 76 is involved in TDP-43 polymerization. Indeed, dimers are formed by head-to-head interactions between NTDs, and the polymer thus obtained allows for pre-mRNA splicing. 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 TDP-43 diseased cells, TDP-43's over-expression leads to the 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. 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. The domain spanning from [1,80] has a solenoid-like structure which sterically impedes interactions between aggregation prone C-term regions. 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.

Mitochondrial localization signal There are six mitochondrial localization signals to be accounted on TDP-43's amino acid sequence, although only M1, M3, and M5 were shown to be essential for mitochondrial 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. 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.

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, which allows them to bind to both RNA and DNA onto U G/T G-repeats of 3'UTR (Untranslated Terminal Regions) end of mRNA/DNA. These sequences mainly ensure mRNA processing, RNA export and RNA stabilizing. It is notably 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.

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.

… excerpt ends here. Continue reading the full article.

Illustrations

Worked examples

Example 1 — a first encounter with TAR DNA-binding protein 43

Start with the simplest possible case. Write down what TAR DNA-binding protein 43 claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to TAR DNA-binding protein 43 before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about TAR DNA-binding protein 43 ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of TAR DNA-binding protein 43

In research: TAR DNA-binding protein 43 appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses TAR DNA-binding protein 43 in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: TAR DNA-binding protein 43 is common in secondary-school and first-year university syllabi. It links to neighbouring topics DNA-binding proteins, Genes on human chromosome 1, so understanding it makes those chapters shorter.
In everyday life: Look for TAR DNA-binding protein 43 outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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Frequently asked questions

What is TAR DNA-binding protein 43 in simple terms?

Transactive response DNA binding protein 43 kDa (TAR DNA-binding protein 43 or TDP-43) is a protein that in humans is encoded by the TARDBP gene. Structure TDP-43 is 414 amino acid residues long.

Why does TAR DNA-binding protein 43 matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study TAR DNA-binding protein 43?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on TAR DNA-binding protein 43.