Intrinsic determinants of prion protein neurotoxicity in Drosophila: from sequence to (dys)function

Prion diseases are fatal brain disorders characterized by deposition of insoluble isoforms the prion protein (PrP). The normal and pathogenic structures PrP relatively well known after decades studies. Yet our current understanding intrinsic determinants regulating misfolding largely missing. A 3D subdomain comprising β2-α2 loop helix 3 contains high sequence structural variability among animals has been proposed as a key domain misfolding. We combined in vivo work Drosophila with molecular dynamics (MD) simulations, which provide additional insight to assess impact candidate substitutions from conformational dynamics. MD simulations revealed that human WT explores multiple β-turn conformations, whereas Y225A (rabbit PrP-like) substitution strongly favors 10 -turn conformation, short right-handed helix. This shift diversity correlates lower neurotoxicity flies. have identified features amino acids toxicity propose new strategy for testing modifiers first followed functional experiments In this review we expand on these results into biology through prism C-terminus. is sensitive measure propensity misfold cause toxicity. provides renewed opportunities identify contribution different states experimental validation transgenic