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| 001 | 140270 | ||
| 005 | 20240722101121.0 | ||
| 024 | 7 | _ | |a 10.1074/jbc.RA118.003440 |2 doi |
| 024 | 7 | _ | |a pmid:30120199 |2 pmid |
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| 024 | 7 | _ | |a 1067-8816 |2 ISSN |
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| 037 | _ | _ | |a DZNE-2020-06592 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 540 |
| 100 | 1 | _ | |a Hans, Friederike |0 P:(DE-2719)2198927 |b 0 |e First author |u dzne |
| 245 | _ | _ | |a Identification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43). |
| 260 | _ | _ | |a Bethesda, Md. |c 2018 |b Soc.60645 |
| 264 | _ | 1 | |3 online |2 Crossref |b American Society for Biochemistry & Molecular Biology (ASBMB) |c 2018-08-17 |
| 264 | _ | 1 | |3 print |2 Crossref |b American Society for Biochemistry & Molecular Biology (ASBMB) |c 2018-10-12 |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1721635866_12032 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 520 | _ | _ | |a TAR DNA-binding protein of 43 kDa (TDP-43) forms pathological aggregates in neurodegenerative diseases, particularly in certain forms of frontotemporal dementia and amyotrophic lateral sclerosis. Pathological modifications of TDP-43 include proteolytic fragmentation, phosphorylation, and ubiquitinylation. A pathognomonic TDP-43 C-terminal fragment (CTF) spanning amino acids 193-414 contains only four lysine residues that could be potentially ubiquitinylated. Here, serial mutagenesis of these four lysines to arginine revealed that not a single residue is responsible for the ubiquitinylation of mCherry-tagged CTF. Removal of all four lysines was necessary to suppress ubiquitinylation. Interestingly, Lys-408 substitution enhanced the pathological phosphorylation of the immediately adjacent serine residues 409/410 in the context of mCherry-CTF. Thus, Lys-408 ubiquitinylation appears to hinder Ser-409/410 phosphorylation in TDP-43 CTF. However, we did not observe the same effect for full-length TDP-43. We extended the mutagenesis study to full-length TDP-43 and performed MS. Ubiquitinylated lysine residues were identified in the nuclear localization sequence (NLS; Lys-84 and Lys-95) and RNA-binding region (mostly Lys-160, Lys-181, and Lys-263). Mutagenesis of Lys-84 confirmed its importance as the major determinant for nuclear import, whereas Lys-95 mutagenesis did not significantly affect TDP-43's nucleo-cytoplasmic distribution, solubility, aggregation, and RNA-processing activities. Nevertheless, the K95A mutant had significantly reduced Ser-409/410 phosphorylation, emphasizing the suspected interplay between TDP-43 ubiquitinylation and phosphorylation. Collectively, our analysis of TDP-43 ubiquitinylation sites indicates that the NLS residues Lys-84 and Lys-95 have more prominent roles in TDP-43 function than the more C-terminal lysines and suggests a link between specific ubiquitinylation events and pathological TDP-43 phosphorylation. |
| 536 | _ | _ | |a 345 - Population Studies and Genetics (POF3-345) |0 G:(DE-HGF)POF3-345 |c POF3-345 |f POF III |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, |
| 650 | _ | 7 | |a DNA-Binding Proteins |2 NLM Chemicals |
| 650 | _ | 7 | |a TDP-43 protein, human |2 NLM Chemicals |
| 650 | _ | 7 | |a Ubiquitin |2 NLM Chemicals |
| 650 | _ | 7 | |a Lysine |0 K3Z4F929H6 |2 NLM Chemicals |
| 650 | _ | 2 | |a Active Transport, Cell Nucleus |2 MeSH |
| 650 | _ | 2 | |a Cell Nucleus: metabolism |2 MeSH |
| 650 | _ | 2 | |a DNA-Binding Proteins: chemistry |2 MeSH |
| 650 | _ | 2 | |a DNA-Binding Proteins: genetics |2 MeSH |
| 650 | _ | 2 | |a DNA-Binding Proteins: metabolism |2 MeSH |
| 650 | _ | 2 | |a HEK293 Cells |2 MeSH |
| 650 | _ | 2 | |a Humans |2 MeSH |
| 650 | _ | 2 | |a Lysine: chemistry |2 MeSH |
| 650 | _ | 2 | |a Mutagenesis, Site-Directed |2 MeSH |
| 650 | _ | 2 | |a Mutation |2 MeSH |
| 650 | _ | 2 | |a Phosphorylation |2 MeSH |
| 650 | _ | 2 | |a Protein Processing, Post-Translational |2 MeSH |
| 650 | _ | 2 | |a Solubility |2 MeSH |
| 650 | _ | 2 | |a Ubiquitin: metabolism |2 MeSH |
| 700 | 1 | _ | |a Eckert, Marita |0 P:(DE-2719)2811929 |b 1 |u dzne |
| 700 | 1 | _ | |a von Zweydorf, Felix |0 P:(DE-2719)2811552 |b 2 |u dzne |
| 700 | 1 | _ | |a Gloeckner, Christian Johannes |0 P:(DE-2719)2811291 |b 3 |u dzne |
| 700 | 1 | _ | |a Kahle, Philipp J |0 P:(DE-2719)2810803 |b 4 |e Last author |u dzne |
| 773 | 1 | 8 | |a 10.1074/jbc.ra118.003440 |b : American Society for Biochemistry & Molecular Biology (ASBMB), 2018-08-17 |n 41 |p 16083-16099 |3 journal-article |2 Crossref |t Journal of Biological Chemistry |v 293 |y 2018 |x 0021-9258 |
| 773 | _ | _ | |a 10.1074/jbc.RA118.003440 |g Vol. 293, no. 41, p. 16083 - 16099 |0 PERI:(DE-600)1474604-9 |n 41 |q 293:41<16083 - 16099 |p 16083-16099 |t The journal of biological chemistry |v 293 |y 2018 |x 0021-9258 |
| 787 | 0 | _ | |a Gloeckner, Christian Johannes |d PRoteomics IDEntifications Database, 2022 |i RelatedTo |0 DZNE-2023-00188 |r |t Mapping of TDP-43 ubiquitination and acetylation sites |
| 856 | 7 | _ | |2 Pubmed Central |u http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187624 |
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| 914 | 1 | _ | |y 2018 |
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| 920 | 1 | _ | |0 I:(DE-2719)1210000-4 |k AG Kahle |l Functional Neurogenetics |x 0 |
| 920 | 1 | _ | |0 I:(DE-2719)1210007 |k AG Gloeckner |l Functional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases |x 1 |
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