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, PrP(C), into a conformationally altered oligomeric form, PrP(Sc). Here we report the crystal structure of the human prion protein in dimer form at 2 A 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 PrP(C) --> PrP(Sc) conversion.
Knaus
K J
KJ
Department of Molecular Cardiology and Center for Structural Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue NB20, Cleveland, Ohio 44195, USA.
Morillas
M
M
Swietnicki
W
W
Malone
M
M
Surewicz
W K
WK
Yee
V C
VC
D018360:Crystallography, X-Ray; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D011328:Prions / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary
D004220:Disulfides; D011328:Prions