Cryo-EM structure of an amyloid fibril formed by full-length human prion protein

Prion diseases are caused by the misfolding of prion protein (PrP). Misfolded PrP forms protease-resistant aggregates in vivo (PrP Sc ) that are able to template the conversion of the native form of the protein (PrP C ), a property shared by in vitro–produced PrP fibrils. Here we produced amyloid fibrils in vitro from recombinant, full-length human PrP C (residues 23–231) and determined their structure using cryo-EM, building a model for the fibril core comprising residues 170−229. The PrP fibril consists of two protofibrils intertwined in a left-handed helix. Lys194 and Glu196 from opposing subunits form salt bridges, creating a hydrophilic cavity at the interface of the two protofibrils. By comparison with the structure of PrP C , we propose that two α-helices in the C-terminal domain of PrP C are converted into β-strands stabilized by a disulfide bond in the PrP fibril. Our data suggest that different PrP mutations may play distinct roles in modulating the conformational conversion. A cryo-EM structure of amyloid fibrils formed in vitro with recombinant human PrP provides insights into fibril architecture and the potential role of disease mutations.