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000006507 0247_ $$2pmid$$apmid:19583211
000006507 0247_ $$2DOI$$a10.1021/bi900901e
000006507 0247_ $$2WOS$$aWOS:000268720300021
000006507 0247_ $$2altmetric$$aaltmetric:3455235
000006507 037__ $$aPreJuSER-6507
000006507 041__ $$aeng
000006507 082__ $$a570
000006507 084__ $$2WoS$$aBiochemistry & Molecular Biology
000006507 1001_ $$0P:(DE-Juel1)VDB72260$$aLeliveld, S. R.$$b0$$uFZJ
000006507 245__ $$aOligomer assembly of the C-terminal DISC1 domain (640-854) is controlled by self-association motifs and disease-associated polymorphism S704C
000006507 260__ $$aColumbus, Ohio$$bAmerican Chemical Society$$c2009
000006507 300__ $$a7746 - 7755
000006507 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
000006507 3367_ $$2DataCite$$aOutput Types/Journal article
000006507 3367_ $$00$$2EndNote$$aJournal Article
000006507 3367_ $$2BibTeX$$aARTICLE
000006507 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000006507 3367_ $$2DRIVER$$aarticle
000006507 440_0 $$0798$$aBiochemistry$$v48$$x0006-2960$$y32
000006507 500__ $$aFunded by a research grant (LE 2197/1-1) to S.R.L. from the German Research Foundation (DFG) and Stanley Medical Research Institute, Baltimore, MD, to C.K.
000006507 520__ $$aGenetic studies have established a role of disrupted-in-schizophrenia-1 (DISC1) in chronic mental diseases (CMD). Limited experimental data are available on the domain structure of the DISC1 protein although multiple interaction partners are known including a self-association domain within the middle part of DISC1 (residues 403-504). The DISC1 C-terminal domain is deleted in the original Scottish pedigree where DISC1 harbors two coiled-coil domains and disease-associated polymorphisms at 607 and 704, as well as the important nuclear distribution element-like 1 (NDEL1) binding site at residues 802-839. Here, we performed mutagenesis studies of the C-terminal domain of the DISC1 protein (residues 640-854) and analyzed the expressed constructs by biochemical and biophysical methods. We identified novel DISC1 self-association motifs and the necessity of their concerted action for orderly assembly: the region 765-854 comprising a coiled-coil domain is a dimerization domain and the region 668-747 an oligomerization domain; dimerization was found to be a prerequisite for orderly assembly of oligomers. Consistent with this, disease-associated polymorphism C704 displayed a slightly higher oligomerization propensity. The heterogeneity of DISC1 multimers in vitro was confirmed with a monoclonal antibody binding exclusively to HMW multimers. We also identified C-terminal DISC1 fragments in human brains, suggesting that C-terminal fragments could carry out DISC1-dependent functions. When the DISC1 C-terminal domain was transiently expressed in cells, it assembled into a range of soluble and insoluble multimers with distinct fractions selectively binding NDEL1, indicating functionality. Our results suggest that assembly of the C-terminal domain is controlled by distinct domains including the disease-associated polymorphism 704 and is functional in vivo.
000006507 536__ $$0G:(DE-Juel1)FUEK409$$2G:(DE-HGF)$$aFunktion und Dysfunktion des Nervensystems$$cP33$$x0
000006507 588__ $$aDataset connected to Web of Science, Pubmed
000006507 650_2 $$2MeSH$$aAnimals
000006507 650_2 $$2MeSH$$aAntibodies, Monoclonal: metabolism
000006507 650_2 $$2MeSH$$aHumans
000006507 650_2 $$2MeSH$$aMice
000006507 650_2 $$2MeSH$$aNerve Tissue Proteins: chemistry
000006507 650_2 $$2MeSH$$aNerve Tissue Proteins: genetics
000006507 650_2 $$2MeSH$$aNerve Tissue Proteins: metabolism
000006507 650_2 $$2MeSH$$aPolymorphism, Genetic
000006507 650_2 $$2MeSH$$aProtein Multimerization
000006507 650_2 $$2MeSH$$aProtein Structure, Quaternary
000006507 650_2 $$2MeSH$$aProtein Structure, Tertiary
000006507 650_7 $$00$$2NLM Chemicals$$aAntibodies, Monoclonal
000006507 650_7 $$00$$2NLM Chemicals$$aDISC1 protein, human
000006507 650_7 $$00$$2NLM Chemicals$$aNerve Tissue Proteins
000006507 650_7 $$2WoSType$$aJ
000006507 7001_ $$0P:(DE-HGF)0$$aHendriks, P.$$b1
000006507 7001_ $$0P:(DE-HGF)0$$aMichel, M.$$b2
000006507 7001_ $$0P:(DE-HGF)0$$aSajnani, G.$$b3
000006507 7001_ $$0P:(DE-HGF)0$$aBader, V.$$b4
000006507 7001_ $$0P:(DE-HGF)0$$aTrossbach, S.$$b5
000006507 7001_ $$0P:(DE-HGF)0$$aPrikulis, I.$$b6
000006507 7001_ $$0P:(DE-Juel1)VDB57647$$aHartmann, R.$$b7$$uFZJ
000006507 7001_ $$0P:(DE-Juel1)VDB20019$$aJonas, E.$$b8$$uFZJ
000006507 7001_ $$0P:(DE-Juel1)132029$$aWillbold, D.$$b9$$uFZJ
000006507 7001_ $$0P:(DE-HGF)0$$aRequena, J. R.$$b10
000006507 7001_ $$0P:(DE-HGF)0$$aKorth, C.$$b11
000006507 773__ $$0PERI:(DE-600)1472258-6$$a10.1021/bi900901e$$gVol. 48, p. 7746 - 7755$$p7746 - 7755$$q48<7746 - 7755$$tBiochemistry$$v48$$x0006-2960$$y2009
000006507 8567_ $$uhttp://dx.doi.org/10.1021/bi900901e
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000006507 915__ $$0StatID:(DE-HGF)0010$$aJCR/ISI refereed
000006507 9141_ $$y2010
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000006507 9201_ $$0I:(DE-Juel1)VDB942$$d31.12.2010$$gISB$$kISB-3$$lStrukturbiochemie$$x0
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