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Cong X, Casiraghi N, Rossetti G, et al. Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein. J Chem Theory Comput. 2013;9(11):5158-67doi: 10.1021/ct400534k.
Cong, X., Casiraghi, N., Rossetti, G., Mohanty, S., Giachin, G., Legname, G., & Carloni, P. (2013). Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein. Journal of chemical theory and computation, 9(11), 5158-67. https://doi.org/10.1021/ct400534k
Cong, Xiaojing, et al. "Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein." Journal of chemical theory and computation vol. 9,11 (2013): 5158-67. doi: https://doi.org/10.1021/ct400534k
Cong X, Casiraghi N, Rossetti G, Mohanty S, Giachin G, Legname G, Carloni P. Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein. J Chem Theory Comput. 2013 Nov 12;9(11):5158-67. doi: 10.1021/ct400534k. Epub 2013 Nov 01. PMID: 26583425.
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J Chem Theory Comput. 2013 Nov 12;9(11):5158-67. doi: 10.1021/ct400534k. Epub 2013 Nov 01.

Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein.

Journal of chemical theory and computation

Xiaojing Cong, Nicola Casiraghi, Giulia Rossetti, Sandipan Mohanty, Gabriele Giachin, Giuseppe Legname, Paolo Carloni

Affiliations

  1. Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) , via Bonomea 265, 34136 Trieste, Italy.
  2. Laboratory for Computational Biophysics, German Research School for Simulation Sciences (GRS) , Forschungszentrum Jülich-RWTH Aachen, 52425 Jülich, Germany.
  3. Computational Biomedicine Section (IAS-5), Institute of Advanced Simulation (IAS) , 52425 Jülich, Germany.
  4. Department of Biology, University of Bologna , via Selmi 3, 40126 Bologna, Italy.
  5. Jülich Supercomputing Centre , Forschungszentrum Jülich, 52425 Jülich, Germany.
  6. Institute for Research in Biomedicine and Barcelona Supercomputing Center Joint Research Program on Computational Biology , Barcelona Science Park, Baldiri I Reixac 10, 08028 Barcelona, Spain.
  7. ELETTRA Laboratory , Sincrotrone Trieste S.C.p.A., 34149 Basovizza, Trieste, Italy.

PMID: 26583425 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 encoding for the prion protein (PrP(C)). Seven PMs are located in the naturally unfolded PrP(C) N-terminal domain, which constitutes about half of the protein. Intriguingly and in sharp contrast to other PMs clustered in the folded domain, N-terminal PMs barely affect the conversion to the pathogenic (scrapie, or PrP(Sc)) isoform of PrP(C). Here, we hypothesize that the neurotoxicity of these PMs arises from changes in structural determinants of the N-terminal domain, affecting the protein binding with its cellular partners and/or the cotranslational translocation during the PrP(C) biosynthesis. We test this idea by predicting the conformational ensemble of the wild-type (WT) and mutated mouse PrP(C) 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 intramolecular contacts in the putative N-terminal domain binding sites for Cu(2+) ions, sulphated glycosaminoglycans, and other known PrP(C) cellular partners. 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 N-terminal PMs affect the PrP(C) binding to functional interactors and/or the translocation.

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