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Mechanistic prospective for human PrPC conversion to PrPSc: Molecular dynamic insights | ||
| Molecular Biology Research Communications | ||
| مقاله 1، دوره 2، شماره 4، اسفند 2013، صفحه 109-122 اصل مقاله (965.98 K) | ||
| نوع مقاله: Original article | ||
| شناسه دیجیتال (DOI): 10.22099/mbrc.2013.1819 | ||
| نویسندگان | ||
| Nooshin Azari1؛ Mohammad Reza Dayer* 2؛ Nematollah Razmi3؛ Mohammad Saaid Dayer4 | ||
| 1Biochemistry Department, Basic Sciences, Fars Science& Research Branch, Islamic Azad University, Shiraz, Islamic Republic of Iran | ||
| 2Department of Biology, Faculty of Science, Shahid Chamran University, Ahvaz, Iran | ||
| 3Biochemistry Department, Basic Sciences, School of Veterinary Medicine, Shiraz University, Shiraz, Islamic Republic of Iran | ||
| 4Department of Parasitology and Medical Entomology, Tarbiat Modares University, Tehran, Islamic Republic of Iran | ||
| چکیده | ||
| PrPC conversion to PrPSc isoform is the main known cause for prion diseases including Crutzfeldt-Jakob, Gerstmann-Sträussler-Sheinker syndrome and fatal familial insomnia in human. The precise mechanism underling this conversion is yet to be well understood. In the present work, using the coordinate file of PrPC (available on the Protein Data Bank) as a starting structure, separate molecular dynamic simulations were carried out at neutral and acidic pH in an explicit water box at 37°C and 1 atmosphere pressure for 10ns second period. Results showed that the acidic pH accelerates PrPC conversion to PrPSc by decreasing the protein gyration radius, flexibility and protein-solvent hydrogen bonds. In acidic conditions, PrPC attains a more folded and less flexible tertiary structure compared to its native structure at neutral pH; otherwise, the decrease of protein-solvent hydrogen bonds at acidic pH will enhance the hydrophobic character of PrPC that may exhibit association as multimeric assemblies. It can also lower water solubility and increase resistance to proteolytic degradations. Data indicated that there was no sensible protein denaturation during this conversion. It is hypothesized that the formation of slightly misfolded conformations with minor structural changes in secondary and/or tertiary structures are enough to menace scrapie formation in PrPC. Our findings show that scrapie formation seems to be a theoretically reversible process. | ||
| کلیدواژهها | ||
| Human Prion Protein؛ Prion Disease؛ pH؛ Misfolded Structure؛ Molecular Dynamic Simulation | ||
| مراجع | ||
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