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transactive response (TAR) DNA-binding protein 43; TDP-43 (TARDBP TDP43)
Function:
- DNA-binding protein & RNA-binding protein
- regulates transcription & splicing
- binds specifically to pyrimidine-rich motifs of TAR DNA & to single stranded TG repeated sequences
- binds to RNA, specifically to UG repeated sequences with a minimun of 6 contiguous repeats
- involved in the regulation of CFTR splicing
- may also be involved in microRNA biogenesis, apoptosis & cell division.
Structure:
- contains 2 RRM domains (RNA recognition motif)
Compartment: nucleus
Expression:
- ubiquitously expressed
- expression is high in pancreas, placenta, lung, genital tract & spleen
Pathology:
1) can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat
2) role in the regulation of CFTR splicing
- promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3' splice site
- this aberrant splicing is associated with pathological features typical of cystic fibrosis
3) hyperphosphorylated, ubiquitinated & cleaved to generate C-terminal fragments in hippocampus, neocortex & spinal cord of patients with amyotrophic lateral sclerosis (ALS)
4) absent from the nucleus of affected neurons in ALS but is the primary component of cytoplasmic ubiquitin-positive inclusion bodies
5) defects in TARDBP are the cause of ALS type 10
6) found in inclusions & neurites of patients with chronic traumatic encephalopathy
7) deposited in brain of patients with frontotemporal dementia (FTD) associated with motor neuron disease
8) associated with proteinopathy in over 20% of people > 80 years, limbic-predominant age-related TDP-43 encephalopathy (LATE) & limbic-predominant amnestic neurodegenerative syndrome (LANS)
9) a misfolded protein relatively common in association with other misfolded proteins amyloid-beta, PHF-tau, & alpha-synuclein in older adults [2]
- the 4 misfolded proteins appear associated with cognitive impairment that typically progresses to severe dementia
Related
TARDBP gene mutation
General
DNA-binding protein
phosphoprotein
RNA-binding protein
Properties
SIZE: entity length = 414 aa
MW = 45 kD
COMPARTMENT: cytoplasm
cell nucleus
MOTIF: Ser phosphorylation site {S91}
Ser phosphorylation site {S92}
RNP motif
NAME: RNP motif
SITE: 104-200
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
NAME: ribonucleoprotein-1 motif
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
ribonucleoprotein-2 motif
ribonucleoprotein-2 motif
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
ribonucleoprotein-2 motif
RNP motif
NAME: RNP motif
SITE: 191-262
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
NAME: ribonucleoprotein-1 motif
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
ribonucleoprotein-2 motif
ribonucleoprotein-2 motif
FOR-BINDING-OF: ribonucleic acid
MOTIF: ribonucleoprotein-1 motif
ribonucleoprotein-2 motif
glycine-rich region {274-413}
Database Correlations
OMIM correlations
MORBIDMAP 605078
UniProt Q13148
Pfam PF00076
Entrez Gene 23435
Kegg hsa:23435
References
- UniProt :accession Q13148
- Karanth S, Nelson PT, Katsumata Y et al
Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins
in Older Adults.
JAMA Neurol. Published online June 22, 2020
PMID: 32568358 Free PMC article
https://jamanetwork.com/journals/jamaneurology/fullarticle/2767373