TAR DNA-binding protein 43

Function

RNA-binding protein that is involved in various steps of RNA biogenesis and processing. Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs. In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases. Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts. Also regulates mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening. In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival. Also participates in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins. Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner. Negatively regulates the expression of CDK6. Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-dependent manner.

Classification

Family (Pfam)

PF00076 RRM_1, PF20910 TDP-43_C, PF18694 TDP-43_N

InterPro

Nucleotide-bd_a/b_plait_sf, RBD_domain_sf, RRM_dom, TDP-43_C, TDP-43_N

Functional cluster

RNA-Polymerase II Transcription Factors

Experimental structures · PDB · 44

• 1WF0 NMR
• 2CQG NMR
• 2N2C NMR
• 2N3X NMR
• 2N4G NMR
• 2N4H NMR
• 2N4P NMR
• 4BS2 NMR
• 4IUF X-ray 2.75A
• 4Y00 X-ray 3.00A
• 4Y0F X-ray 2.65A
• 5MDI X-ray 2.10A
• … and 32 more

A predicted model is available from AlphaFold.

Gene Ontology · 36

• GO:0000785 chromatin
• GO:0010494 cytoplasmic stress granule
• GO:0035061 interchromatin granule
• GO:0005739 mitochondrion
• GO:0016607 nuclear speck
• GO:0005654 nucleoplasm
• GO:0005634 nucleus
• GO:0005726 perichromatin fibrils
• GO:0003677 DNA binding
• GO:0003690 double-stranded DNA binding
• GO:0042802 identical protein binding
• GO:0008289 lipid binding
• GO:0140693 molecular condensate scaffold activity
• GO:0003730 mRNA 3'-UTR binding
• GO:0097157 pre-mRNA intronic binding
• GO:0003723 RNA binding
• GO:0000978 RNA polymerase II cis-regulatory region sequence-specific DNA binding
• GO:0061158 3'-UTR-mediated mRNA destabilization
• GO:0070935 3'-UTR-mediated mRNA stabilization
• GO:1990000 amyloid fibril formation
• GO:0006351 DNA-templated transcription
• GO:0043922 host-mediated suppression of viral transcription
• GO:0006397 mRNA processing
• GO:0010629 negative regulation of gene expression
• GO:0001933 negative regulation of protein phosphorylation
• GO:0071765 nuclear inner membrane organization
• GO:0032024 positive regulation of insulin secretion
• GO:0042307 positive regulation of protein import into nucleus
• GO:0042981 regulation of apoptotic process
• GO:0051726 regulation of cell cycle
• GO:0042752 regulation of circadian rhythm
• GO:0010468 regulation of gene expression
• GO:0031647 regulation of protein stability
• GO:0034976 response to endoplasmic reticulum stress
• GO:0048511 rhythmic process
• GO:0008380 RNA splicing

Disease associations

• amyotrophic lateral sclerosis type 10 MONDO:0012790

Neighborhood · nearest proteins

Related proteins · sequence + function similarity

• TAR DNA-binding protein 43 1.00
• TAR DNA-binding protein 43 0.99
• TAR DNA-binding protein 43 0.99
• TAR DNA-binding protein 43 0.97
• Polyadenylate-binding protein RBP47 0.71
• Heterogeneous nuclear ribonucleoprotein H2 0.69
• Heterogeneous nuclear ribonucleoprotein H2 0.69
• Heterogeneous nuclear ribonucleoprotein H2 0.69
• Heterogeneous nuclear ribonucleoprotein H2 0.69
• Heterogeneous nuclear ribonucleoprotein H2 0.69
• Polyadenylate-binding protein RBP45A 0.68
• Polyadenylate-binding protein RBP47A 0.68

Co-cited proteins · studied together in the literature

• TAR DNA-binding protein 43 3 shared papers
• Ataxin-2 1 shared papers
• Superoxide dismutase [Cu-Zn] 1 shared papers
• CCR4-NOT transcription complex subunit 7 1 shared papers
• Heterogeneous nuclear ribonucleoproteins A2/B1 2 shared papers
• Ubiquilin-2 1 shared papers
• Lamin-B1 1 shared papers
• Matrin-3 1 shared papers
• BTB/POZ domain-containing protein KCTD5 1 shared papers
• Cyclic GMP-AMP synthase 1 shared papers
• Heterogeneous nuclear ribonucleoprotein M 1 shared papers
• Peptidyl-prolyl cis-trans isomerase A 1 shared papers

Literature · 51 cited papers

• TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS. Cell · 2020
• TDP-43 accelerates deadenylation of target mRNAs by recruiting Caf1 deadenylase. FEBS Lett. · 2019
• TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature · 2018
• Atomic-level evidence for packing and positional amyloid polymorphism by segment from TDP-43 RRM2. Nat. Struct. Mol. Biol. · 2018
• A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J. · 2018
• TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Sci. Rep. · 2017
• Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation. Nat. Commun. · 2017
• Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat. Struct. Mol. Biol. · 2017
• USP7 and TDP-43: pleiotropic regulation of cryptochrome protein stability paces the oscillation of the mammalian circadian clock. PLoS ONE · 2016
• SUMO-2 orchestrates chromatin modifiers in response to DNA damage. Cell Rep. · 2015
• Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes. Brain · 2015
• Uncovering global SUMOylation signaling networks in a site-specific manner. Nat. Struct. Mol. Biol. · 2014
• … and 39 more in the literature graph