000062864 001__ 62864
000062864 005__ 20200402210514.0
000062864 0247_ $$2pmid$$apmid:18473442
000062864 0247_ $$2DOI$$a10.1021/bi800253c
000062864 0247_ $$2WOS$$aWOS:000256405800020
000062864 037__ $$aPreJuSER-62864
000062864 041__ $$aeng
000062864 082__ $$a570
000062864 084__ $$2WoS$$aBiochemistry & Molecular Biology
000062864 1001_ $$0P:(DE-Juel1)VDB72260$$aLeliveld, S. R.$$b0$$uFZJ
000062864 245__ $$aExpansion of the octarepeat domain alters the misfolding pathway but not the folding pathway of the prion protein
000062864 260__ $$aColumbus, Ohio$$bAmerican Chemical Society$$c2008
000062864 300__ $$a6267 - 6278
000062864 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article
000062864 3367_ $$2DataCite$$aOutput Types/Journal article
000062864 3367_ $$00$$2EndNote$$aJournal Article
000062864 3367_ $$2BibTeX$$aARTICLE
000062864 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000062864 3367_ $$2DRIVER$$aarticle
000062864 440_0 $$0798$$aBiochemistry$$v47$$x0006-2960$$y23
000062864 500__ $$aRecord converted from VDB: 12.11.2012
000062864 520__ $$aA misfolded conformation of the prion protein (PrP), PrP (Sc), is the essential component of prions, the infectious agents that cause transmissible neurodegenerative diseases. Insertional mutations that lead to an increase in the number of octarepeats (ORs) in PrP are linked to familial human prion disease. In this study, we investigated how expansion of the OR domain causes PrP to favor a prion-like conformation. Therefore, we compared the conformational and aggregation modulating properties of wild-type versus expanded OR domains, either as a fusion construct with the protein G B1 domain (GB1-OR) or as an integral part of full-length mouse PrP (MoPrP). Using circular dichroism spectroscopy, we first demonstrated that ORs are not unfolded but exist as an ensemble of three distinct conformers: polyproline helix-like, beta-turn, and "Trp-related". Domain expansion had little effect on the conformation of GB1-OR fusion proteins. When part of MoPrP however, OR domain expansion changed PrP's folding landscape, not by hampering the production of native alpha-helical monomers but by greatly reducing the propensity to form amyloid and by altering the assembly of misfolded, beta-rich aggregates. These features may relate to subtle pH-dependent conformational differences between wild-type and mutant monomers. In conclusion, we propose that PrP insertional mutations are pathogenic because they enhance specific misfolding pathways of PrP rather than by undermining native folding. This idea was supported by a trial bioassay in transgenic mice overexpressing wild-type MoPrP, where intracerebral injection of recombinant MoPrP with an expanded OR domain but not wild-type MoPrP caused prion disease.
000062864 536__ $$0G:(DE-Juel1)FUEK409$$2G:(DE-HGF)$$aFunktion und Dysfunktion des Nervensystems$$cP33$$x0
000062864 588__ $$aDataset connected to Web of Science, Pubmed
000062864 650_2 $$2MeSH$$aAnimals
000062864 650_2 $$2MeSH$$aCircular Dichroism
000062864 650_2 $$2MeSH$$aKinetics
000062864 650_2 $$2MeSH$$aMice
000062864 650_2 $$2MeSH$$aMutagenesis, Insertional
000062864 650_2 $$2MeSH$$aOpen Reading Frames
000062864 650_2 $$2MeSH$$aPrPSc Proteins: chemistry
000062864 650_2 $$2MeSH$$aPrPSc Proteins: genetics
000062864 650_2 $$2MeSH$$aPrPSc Proteins: metabolism
000062864 650_2 $$2MeSH$$aPrions: chemistry
000062864 650_2 $$2MeSH$$aPrions: genetics
000062864 650_2 $$2MeSH$$aPrions: metabolism
000062864 650_2 $$2MeSH$$aProtein Conformation
000062864 650_2 $$2MeSH$$aProtein Denaturation
000062864 650_2 $$2MeSH$$aProtein Folding
000062864 650_2 $$2MeSH$$aRecombinant Proteins: chemistry
000062864 650_2 $$2MeSH$$aRepetitive Sequences, Amino Acid
000062864 650_2 $$2MeSH$$aThrombin
000062864 650_7 $$00$$2NLM Chemicals$$aPrPSc Proteins
000062864 650_7 $$00$$2NLM Chemicals$$aPrions
000062864 650_7 $$00$$2NLM Chemicals$$aRecombinant Proteins
000062864 650_7 $$0EC 3.4.21.5$$2NLM Chemicals$$aThrombin
000062864 650_7 $$2WoSType$$aJ
000062864 7001_ $$0P:(DE-HGF)0$$aStitz, L.$$b1
000062864 7001_ $$0P:(DE-Juel1)VDB72259$$aKorth, C.$$b2$$uFZJ
000062864 773__ $$0PERI:(DE-600)1472258-6$$a10.1021/bi800253c$$gVol. 47, p. 6267 - 6278$$p6267 - 6278$$q47<6267 - 6278$$tBiochemistry$$v47$$x0006-2960$$y2008
000062864 8567_ $$uhttp://dx.doi.org/10.1021/bi800253c
000062864 909CO $$ooai:juser.fz-juelich.de:62864$$pVDB
000062864 9131_ $$0G:(DE-Juel1)FUEK409$$bGesundheit$$kP33$$lFunktion und Dysfunktion des Nervensystems$$vFunktion und Dysfunktion des Nervensystems$$x0
000062864 9141_ $$y2008
000062864 915__ $$0StatID:(DE-HGF)0010$$aJCR/ISI refereed
000062864 9201_ $$0I:(DE-Juel1)VDB805$$d31.12.2008$$gINB$$kINB-2$$lMolekulare Biophysik$$x0
000062864 970__ $$aVDB:(DE-Juel1)99747
000062864 980__ $$aVDB
000062864 980__ $$aConvertedRecord
000062864 980__ $$ajournal
000062864 980__ $$aI:(DE-Juel1)ISB-2-20090406
000062864 980__ $$aUNRESTRICTED
000062864 980__ $$aI:(DE-Juel1)ICS-6-20110106
000062864 981__ $$aI:(DE-Juel1)IBI-7-20200312
000062864 981__ $$aI:(DE-Juel1)ISB-2-20090406
000062864 981__ $$aI:(DE-Juel1)ICS-6-20110106