Prion Protein (2021-03-12)

Abstract

The prion protein is part of a small group of similar proteins present in mammals,where it plays a significant yet unclear role in their nervous system. All prionproteins consist of both a structured and unstructured domain. Theirtransformation within the structured domain from a normal cellular prion proteinconformation (PrPC) to their toxic aggregated amyloid scrapie conformation(PrPSC) causes several different transmissible spongiform encephalopathies(TSEs). The region of the structured 3D domain near the C-terminus, consisting ofa ?2-?2 loop and a distal helix 3, is thought to play an important role in themisfolding of PrPC to PrPSC. PrP exhibits a range of neurotoxicity, human PrPbeing the most toxic, while other mammals such as horse and rabbit show highdegree of resistance. The sequence alignment of several mammals’ PrP revealthirteen amino acids that are unique to human in the structured domain. Thisresearch focuses on utilizing molecular dynamics (MD), metadynamics (MetaD),and temperature – replica exchange molecular dynamics (t-remd) to study theeffect of some of these mutations on the conformations of the ?2-?2 loop.Comparing the mutants M166V, D167S, M166V-D167S, and M166V-Y225A to thehuman prion protein (wild type) allows us to identify which amino acids stabilizedifferent conformations. The results of this study indicate that the wild typesamples a protected 310helical turn conformation and several ?-turnconformations. The results from the mutants suggest that the point mutation ofM166V assists in keeping the ?2-?2 loop primarily in the protected 310 helical turnconformation. These results provide a mechanistic basis describing the effects ofmutations on the stability of the C-terminus region of PrP, which can be tested byrational design of new mutants in fruit fly models.