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

ABSTRACT: Prion diseases are fatal brain disorders characterized by deposition of insoluble isoforms of the prion protein (PrP). The normal and pathogenic structures of PrP are relatively well known after decades of studies. Yet our current understanding of the intrinsic determinants regulating PrP misfolding are largely missing. A 3D subdomain of PrP comprising the β2-α2 loop and helix 3 contains high sequence and structural variability among animals and has been proposed as a key domain regulating PrP misfolding. We combined in vivo work in Drosophila with molecular dynamics (MD) simulations, which provide additional insight to assess the impact of candidate substitutions in PrP from conformational dynamics. MD simulations revealed that in human PrP WT the β2-α2 loop explores multipl

SUBMITTER: Cembran A 

PROVIDER: S-EPMC10461008 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature