title: Role of Prion Disease-Linked Mutations in the Intrinsically Disordered N-Terminal Domain of the Prion Protein.
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.
authors.affiliation: Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) , via Bonomea 265, 34136 Trieste, Italy.|Laboratory for Computational Biophysics, German Research School for Simulation Sciences (GRS) , Forschungszentrum Jülich-RWTH Aachen, 52425 Jülich, Germany.|Computational Biomedicine Section (IAS-5), Institute of Advanced Simulation (IAS) , 52425 Jülich, Germany.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Cong
authors.affiliation: Laboratory for Computational Biophysics, German Research School for Simulation Sciences (GRS) , Forschungszentrum Jülich-RWTH Aachen, 52425 Jülich, Germany.|Department of Biology, University of Bologna , via Selmi 3, 40126 Bologna, Italy.|Computational Biomedicine Section (IAS-5), Institute of Advanced Simulation (IAS) , 52425 Jülich, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Casiraghi
authors.affiliation: Laboratory for Computational Biophysics, German Research School for Simulation Sciences (GRS) , Forschungszentrum Jülich-RWTH Aachen, 52425 Jülich, Germany.|Jülich Supercomputing Centre , Forschungszentrum Jülich, 52425 Jülich, Germany.|Computational Biomedicine Section (IAS-5), Institute of Advanced Simulation (IAS) , 52425 Jülich, Germany.|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.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Jülich Supercomputing Centre , Forschungszentrum Jülich, 52425 Jülich, Germany.
authors.forename: Sandipan
authors.initials: S
authors.lastname: Mohanty
authors.affiliation: Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) , via Bonomea 265, 34136 Trieste, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Giachin
authors.affiliation: Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA) , via Bonomea 265, 34136 Trieste, Italy.|ELETTRA Laboratory , Sincrotrone Trieste S.C.p.A., 34149 Basovizza, Trieste, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.affiliation: Laboratory for Computational Biophysics, German Research School for Simulation Sciences (GRS) , Forschungszentrum Jülich-RWTH Aachen, 52425 Jülich, Germany.|Computational Biomedicine Section (IAS-5), Institute of Advanced Simulation (IAS) , 52425 Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni