- Glynn, Calina;
- Sawaya, Michael R;
- Ge, Peng;
- Gallagher-Jones, Marcus;
- Short, Connor W;
- Bowman, Ronquiajah;
- Apostol, Marcin;
- Zhou, Z Hong;
- Eisenberg, David S;
- Rodriguez, Jose A
Self-templating assemblies of the human prion protein are clinically associated with transmissible spongiform encephalopathies. Here we present the cryo-EM structure of a denaturant- and protease-resistant fibril formed in vitro spontaneously by a 9.7-kDa unglycosylated fragment of the human prion protein. This human prion fibril contains two protofilaments intertwined with screw symmetry and linked by a tightly packed hydrophobic interface. Each protofilament consists of an extended beta arch formed by residues 106 to 145 of the prion protein, a hydrophobic and highly fibrillogenic disease-associated segment. Such structures of prion polymorphs serve as blueprints on which to evaluate the potential impact of sequence variants on prion disease.