Common structural traits across pathogenic mutants of the human prion protein and their implications for familial prion diseases |
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Authors: | Rossetti Giulia Cong Xiaojing Caliandro Rocco Legname Giuseppe Carloni Paolo |
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Affiliation: | 1 Statistical and Biological Physics Sector, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, I-34136 Trieste, Italy2 CNR-INFM-Democritos National Simulation Center, Via Bonomea 265, I-34136 Trieste, Italy3 Italian Institute of Technology, SISSA Unit, Via Bonomea 265, I-34136 Trieste, Italy4 German Research School for Simulation Science, FZ-Jülich and RWTH Aachen, Wilhelm-Johnen-Straße, 52428 Jülich, Germany5 CNR Institute of Crystallography, via Amendola 122/o, I-70126 Bari, Italy6 ELETTRA Laboratory, Sincrotrone Trieste S.C.p.A., I-34149, Basovizza, Trieste, Italy7 Laboratory of Prion Biology, Neurobiology Sector, SISSA, Via Bonomea 265, I-34136 Trieste, Italy |
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Abstract: | Human (Hu) familial prion diseases are associated with about 40 point mutations of the gene coding for the prion protein (PrP). Most of the variants associated with these mutations are located in the globular domain of the protein. We performed 50 ns of molecular dynamics for each of these mutants to investigate their structure in aqueous solution. Overall, 1.6 μs of molecular dynamics data is presented. The calculations are based on the AMBER(parm99) force field, which has been shown to reproduce very accurately the structural features of the HuPrP wild type and a few variants for which experimental structural information is available. The variants present structural determinants different from those of wild-type HuPrP and the protective mutation HuPrP(E219K-129M). These include the loss of salt bridges in α2-α3 regions and the loss of π-stacking interactions in the β2-α2 loop. In addition, in the majority of the mutants, the α3 helix is more flexible and Y169 is more solvent exposed. The presence of similar traits in this large spectrum of mutations hints to a role of these fingerprints in their known disease-causing properties. Overall, the regions most affected by disease-linked mutations in terms of structure and/or flexibility are those involved in the pathogenic conversion to the scrapie form of the protein and in the interaction with cellular partners. These regions thus emerge as optimal targets for antibody- and ligand-binding studies. |
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Keywords: | PrP, prion protein GD, globular domain DLM, disease-linked mutation WT, wild type MD, molecular dynamics HuPrP(PP), HuPrP(E219K-129M) RMSF, root-mean-square fluctuation SB, salt bridge ADI, angular dispersion index HB, hydrogen bond |
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