Crystal structure of the human prion protein reveals a mechanism for oligomerization

The pathogenesis of transmissible encephalopathies is associated with the conversion of the cellular prion protein, PrPC, into a conformationally altered oligomeric form, PrPSc. Here we report the crystal structure of the human prion protein in dimer form at 2 Angstrom resolution. The dimer results from the three-dimensional swapping of the C-terminal helix 3 and rearrangement of the disulfide bond. An interchain two-stranded antiparallel beta -sheet is formed at the dimer interface by residues that are located in helix 2 in the monomeric NMR structures. Familial prion disease mutations map to the regions directly involved in helix swapping. This crystal structure suggests that oligomerization through 3D domain-swapping may constitute an important step on the pathway of the PrPC --> PrPSc conversion.