guest ::
| Home > Publications database > Role of prion disease-linked mutations in the intrinsically disordered N-terminal domain of the prion protein |
| Home > Publications database > Role of prion disease-linked mutations in the intrinsically disordered N-terminal domain of the prion protein |
| Journal Article | FZJ-2013-04794 |
; ; ; ; ; ;
2013
American Chemical Society (ACS)
Washington, DC
This record in other databases: 
Please use a persistent id in citations: doi:10.1021/ct400534k
Abstract: Prion diseases are fatal neurodegenerative disorders in mammals and other animal species. In humans, about 15% of these maladies are caused by pathogenic mutations (PMs) in the gene coding for the prion protein. Seven PMs are located in the naturally unfolded N-terminal domain, which constitutes about half of the protein. Intriguingly, and in sharp contrast to other PMs, they do not affect the in vitro conversion towards the pathogenic ('scrapie') form of the prion protein. Here we hypothesize that the neurotoxicity of these PMs arises from changes in structural determinants of the N-terminal domain, which affect the protein binding with its cellular partners and/or the co-translational translocation during the biosynthesis of the protein. We test this idea by predicting the conformational ensemble of wild-type (WT) and mutated mouse prion protein's N-terminal domain, whose sequence is almost identical to that of the human one and for which the largest number of in vivo data is available. The conformational properties of the WT are consistent with those inferred experimentally. Importantly, the PMs turn out to affect in a subtle manner the intra-molecular contacts in the putative N-terminal domain’s binding sites for Cu2+ ions, sulphated glycosaminoglycans and other known prion protein’s cellular partners in vivo. The PMs also alter the local structural features of the transmembrane domain and adjacent stop transfer effector, which act together to regulate the protein topology. These results corroborate the hypothesis that PMs affect the prion protein binding to its functional interactors and/or the translocation.
; JCR ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record
|
The record appears in these collections: |
PDF