PrP N-terminal domain triggers PrP Sc-like aggregation of Dpl

Abstract

Transmissible spongiform encephalopathies are fatal neurodegenerative disorders thought to be transmitted by self-perpetuating conformational conversion of a neuronal membrane glycoprotein (PrP C, for “cellular prion protein”) into an abnormal state (PrP Sc, for “scrapie prion protein”). Doppel (Dpl) is a protein that shares significant biochemical and structural homology with PrP C. In contrast to its homologue PrP C, Dpl is unable to participate in prion disease progression or to achieve an abnormal PrP Sc-like state. We have constructed a chimeric mouse protein, composed of the N-terminal domain of PrP C (residues 23–125) and the C-terminal part of Dpl (residues 58–157). This chimeric protein displays PrP-like biochemical and structural features; when incubated in presence of NaCl, the α-helical monomer forms soluble β-sheet-rich oligomers which acquire partial resistance to pepsin proteolysis in vitro, as do PrP oligomers. Moreover, the presence of aggregates akin to protofibrils is observed in soluble oligomeric species by electron microscopy.