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000136697 0247_ $$2doi$$a10.1038/emboj.2012.261
000136697 0247_ $$2pmid$$apmid:22968170
000136697 0247_ $$2pmc$$apmc:PMC3501225
000136697 0247_ $$2ISSN$$a0261-4189
000136697 0247_ $$2ISSN$$a1460-2075
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000136697 037__ $$aDZNE-2020-03019
000136697 041__ $$aEnglish
000136697 082__ $$a570
000136697 1001_ $$0P:(DE-2719)9000059$$aDormann, Dorothee$$b0$$eFirst author
000136697 245__ $$aArginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS.
000136697 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2012
000136697 264_1 $$2Crossref$$3online$$bWiley$$c2012-09-11
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000136697 3367_ $$2ORCID$$aJOURNAL_ARTICLE
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000136697 520__ $$aFused in sarcoma (FUS) is a nuclear protein that carries a proline-tyrosine nuclear localization signal (PY-NLS) and is imported into the nucleus via Transportin (TRN). Defects in nuclear import of FUS have been implicated in neurodegeneration, since mutations in the PY-NLS of FUS cause amyotrophic lateral sclerosis (ALS). Moreover, FUS is deposited in the cytosol in a subset of frontotemporal lobar degeneration (FTLD) patients. Here, we show that arginine methylation modulates nuclear import of FUS via a novel TRN-binding epitope. Chemical or genetic inhibition of arginine methylation restores TRN-mediated nuclear import of ALS-associated FUS mutants. The unmethylated arginine-glycine-glycine domain preceding the PY-NLS interacts with TRN and arginine methylation in this domain reduces TRN binding. Inclusions in ALS-FUS patients contain methylated FUS, while inclusions in FTLD-FUS patients are not methylated. Together with recent findings that FUS co-aggregates with two related proteins of the FET family and TRN in FTLD-FUS but not in ALS-FUS, our study provides evidence that these two diseases may be initiated by distinct pathomechanisms and implicates alterations in arginine methylation in pathogenesis.
000136697 536__ $$0G:(DE-HGF)POF3-344$$a344 - Clinical and Health Care Research (POF3-344)$$cPOF3-344$$fPOF III$$x0
000136697 542__ $$2Crossref$$i2015-09-01$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000136697 650_7 $$2NLM Chemicals$$aKaryopherins
000136697 650_7 $$2NLM Chemicals$$aNuclear Localization Signals
000136697 650_7 $$2NLM Chemicals$$aRNA-Binding Protein FUS
000136697 650_7 $$2NLM Chemicals$$aRepressor Proteins
000136697 650_7 $$042HK56048U$$2NLM Chemicals$$aTyrosine
000136697 650_7 $$094ZLA3W45F$$2NLM Chemicals$$aArginine
000136697 650_7 $$09DLQ4CIU6V$$2NLM Chemicals$$aProline
000136697 650_7 $$0EC 2.1.1.319$$2NLM Chemicals$$aPRMT1 protein, human
000136697 650_7 $$0EC 2.1.1.319$$2NLM Chemicals$$aProtein-Arginine N-Methyltransferases
000136697 650_2 $$2MeSH$$aActive Transport, Cell Nucleus
000136697 650_2 $$2MeSH$$aAmino Acid Sequence
000136697 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000136697 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000136697 650_2 $$2MeSH$$aArginine: metabolism
000136697 650_2 $$2MeSH$$aCell Nucleus: metabolism
000136697 650_2 $$2MeSH$$aFrontotemporal Lobar Degeneration: metabolism
000136697 650_2 $$2MeSH$$aGene Silencing
000136697 650_2 $$2MeSH$$aHeLa Cells
000136697 650_2 $$2MeSH$$aHumans
000136697 650_2 $$2MeSH$$aKaryopherins: genetics
000136697 650_2 $$2MeSH$$aKaryopherins: metabolism
000136697 650_2 $$2MeSH$$aMethylation
000136697 650_2 $$2MeSH$$aMolecular Sequence Data
000136697 650_2 $$2MeSH$$aNuclear Localization Signals: metabolism
000136697 650_2 $$2MeSH$$aProline: metabolism
000136697 650_2 $$2MeSH$$aProtein Binding
000136697 650_2 $$2MeSH$$aProtein-Arginine N-Methyltransferases: genetics
000136697 650_2 $$2MeSH$$aProtein-Arginine N-Methyltransferases: metabolism
000136697 650_2 $$2MeSH$$aRNA-Binding Protein FUS: genetics
000136697 650_2 $$2MeSH$$aRNA-Binding Protein FUS: metabolism
000136697 650_2 $$2MeSH$$aRepressor Proteins: genetics
000136697 650_2 $$2MeSH$$aRepressor Proteins: metabolism
000136697 650_2 $$2MeSH$$aSignal Transduction
000136697 650_2 $$2MeSH$$aTyrosine: metabolism
000136697 7001_ $$0P:(DE-HGF)0$$aMadl, Tobias$$b1
000136697 7001_ $$0P:(DE-2719)2810632$$aValori, Chiara F$$b2
000136697 7001_ $$0P:(DE-HGF)0$$aBentmann, Eva$$b3
000136697 7001_ $$0P:(DE-HGF)0$$aTahirovic, Sabina$$b4
000136697 7001_ $$0P:(DE-HGF)0$$aAbou-Ajram, Claudia$$b5
000136697 7001_ $$0P:(DE-HGF)0$$aKremmer, Elisabeth$$b6
000136697 7001_ $$0P:(DE-HGF)0$$aAnsorge, Olaf$$b7
000136697 7001_ $$0P:(DE-HGF)0$$aMackenzie, Ian R A$$b8
000136697 7001_ $$0P:(DE-2719)2810592$$aNeumann, Manuela$$b9
000136697 7001_ $$0P:(DE-HGF)0$$aHaass, Christian$$b10
000136697 77318 $$2Crossref$$3journal-article$$a10.1038/emboj.2012.261$$b : Wiley, 2012-09-11$$n22$$p4258-4275$$tThe EMBO Journal$$v31$$x0261-4189$$y2012
000136697 773__ $$0PERI:(DE-600)1467419-1$$a10.1038/emboj.2012.261$$gVol. 31, no. 22, p. 4258 - 4275$$n22$$p4258-4275$$q31:22<4258 - 4275$$tThe EMBO journal$$v31$$x0261-4189$$y2012
000136697 8567_ $$2Pubmed Central$$uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501225
000136697 8564_ $$uhttps://pub.dzne.de/record/136697/files/DZNE-2020-03019_Restricted.pdf
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000136697 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)9000059$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b0$$kDZNE
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000136697 9141_ $$y2012
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000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/nprot.2006.356$$o10.1038/nprot.2006.356
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/S0140-6736(10)61156-7$$o10.1016/S0140-6736(10)61156-7
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/nar/gkq1162$$o10.1093/nar/gkq1162
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1016/j.chembiol.2008.07.019$$o10.1016/j.chembiol.2008.07.019
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1038/emboj.2010.167$$o10.1038/emboj.2010.167
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1126/science.1166066$$o10.1126/science.1166066
000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/hmg/ddq137$$o10.1093/hmg/ddq137
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000136697 999C5 $$2Crossref$$oNeumann 2012$$y2012
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000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1093/nar/gki380$$o10.1093/nar/gki380
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000136697 999C5 $$2Crossref$$9-- missing cx lookup --$$a10.1073/pnas.1207247109$$o10.1073/pnas.1207247109