000140270 001__ 140270
000140270 005__ 20240722101121.0
000140270 0247_ $$2doi$$a10.1074/jbc.RA118.003440
000140270 0247_ $$2pmid$$apmid:30120199
000140270 0247_ $$2pmc$$apmc:PMC6187624
000140270 0247_ $$2ISSN$$a0021-9258
000140270 0247_ $$2ISSN$$a1067-8816
000140270 0247_ $$2ISSN$$a1083-351X
000140270 0247_ $$2altmetric$$aaltmetric:46699446
000140270 037__ $$aDZNE-2020-06592
000140270 041__ $$aEnglish
000140270 082__ $$a540
000140270 1001_ $$0P:(DE-2719)2198927$$aHans, Friederike$$b0$$eFirst author$$udzne
000140270 245__ $$aIdentification and characterization of ubiquitinylation sites in TAR DNA-binding protein of 43 kDa (TDP-43).
000140270 260__ $$aBethesda, Md.$$bSoc.60645$$c2018
000140270 264_1 $$2Crossref$$3online$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2018-08-17
000140270 264_1 $$2Crossref$$3print$$bAmerican Society for Biochemistry & Molecular Biology (ASBMB)$$c2018-10-12
000140270 3367_ $$2DRIVER$$aarticle
000140270 3367_ $$2DataCite$$aOutput Types/Journal article
000140270 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1721635866_12032
000140270 3367_ $$2BibTeX$$aARTICLE
000140270 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000140270 3367_ $$00$$2EndNote$$aJournal Article
000140270 520__ $$aTAR 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.
000140270 536__ $$0G:(DE-HGF)POF3-345$$a345 - Population Studies and Genetics (POF3-345)$$cPOF3-345$$fPOF III$$x0
000140270 588__ $$aDataset connected to CrossRef, PubMed,
000140270 650_7 $$2NLM Chemicals$$aDNA-Binding Proteins
000140270 650_7 $$2NLM Chemicals$$aTDP-43 protein, human
000140270 650_7 $$2NLM Chemicals$$aUbiquitin
000140270 650_7 $$0K3Z4F929H6$$2NLM Chemicals$$aLysine
000140270 650_2 $$2MeSH$$aActive Transport, Cell Nucleus
000140270 650_2 $$2MeSH$$aCell Nucleus: metabolism
000140270 650_2 $$2MeSH$$aDNA-Binding Proteins: chemistry
000140270 650_2 $$2MeSH$$aDNA-Binding Proteins: genetics
000140270 650_2 $$2MeSH$$aDNA-Binding Proteins: metabolism
000140270 650_2 $$2MeSH$$aHEK293 Cells
000140270 650_2 $$2MeSH$$aHumans
000140270 650_2 $$2MeSH$$aLysine: chemistry
000140270 650_2 $$2MeSH$$aMutagenesis, Site-Directed
000140270 650_2 $$2MeSH$$aMutation
000140270 650_2 $$2MeSH$$aPhosphorylation
000140270 650_2 $$2MeSH$$aProtein Processing, Post-Translational
000140270 650_2 $$2MeSH$$aSolubility
000140270 650_2 $$2MeSH$$aUbiquitin: metabolism
000140270 7001_ $$0P:(DE-2719)2811929$$aEckert, Marita$$b1$$udzne
000140270 7001_ $$0P:(DE-2719)2811552$$avon Zweydorf, Felix$$b2$$udzne
000140270 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b3$$udzne
000140270 7001_ $$0P:(DE-2719)2810803$$aKahle, Philipp J$$b4$$eLast author$$udzne
000140270 77318 $$2Crossref$$3journal-article$$a10.1074/jbc.ra118.003440$$b : American Society for Biochemistry & Molecular Biology (ASBMB), 2018-08-17$$n41$$p16083-16099$$tJournal of Biological Chemistry$$v293$$x0021-9258$$y2018
000140270 773__ $$0PERI:(DE-600)1474604-9$$a10.1074/jbc.RA118.003440$$gVol. 293, no. 41, p. 16083 - 16099$$n41$$p16083-16099$$q293:41<16083 - 16099$$tThe journal of biological chemistry$$v293$$x0021-9258$$y2018
000140270 7870_ $$0DZNE-2023-00188$$aGloeckner, Christian Johannes$$dPRoteomics IDEntifications Database, 2022$$iRelatedTo$$r$$tMapping of TDP-43 ubiquitination and acetylation sites
000140270 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187624
000140270 909CO $$ooai:pub.dzne.de:140270$$pVDB
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000140270 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810803$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b4$$kDZNE
000140270 9131_ $$0G:(DE-HGF)POF3-345$$1G:(DE-HGF)POF3-340$$2G:(DE-HGF)POF3-300$$3G:(DE-HGF)POF3$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lErkrankungen des Nervensystems$$vPopulation Studies and Genetics$$x0
000140270 9141_ $$y2018
000140270 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bJ BIOL CHEM : 2019$$d2021-05-04
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000140270 9201_ $$0I:(DE-2719)1210000-4$$kAG Kahle$$lFunctional Neurogenetics$$x0
000140270 9201_ $$0I:(DE-2719)1210007$$kAG Gloeckner$$lFunctional Neuroproteomics and Translational Biomarkers in Neurodegenerative Diseases$$x1
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