Solution structure of the E200K variant of human prion protein - Implications for the mechanism of pathogenesis in familial prion diseases

Prion propagation in transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrPC, into a pathogenic conformer, P rPSc. Hereditary forms of the disease are Linked to specific mutations in t he gene coding for the prion protein. To gain insight into the molecular ba sis of these disorders, the solution structure of the familial Creutzfeldt- Jakob disease-related E200K variant of human prion protein was determined b y multi-dimensional nuclear magnetic resonance spectroscopy, Remarkably, ap art from minor differences in flexible regions, the backbone tertiary struc ture of the E200K variant is nearly identical to that reported for the wild -type human prion protein, The only major consequence of the mutation is th e perturbation of surface electrostatic potential. The present structural d ata strongly suggest that protein surface defects leading to abnormalities in the interaction of prion protein with auxiliary proteins/chaperones or c ellular membranes should be considered key determinants of a spontaneous Pr PC --> PrPSc conversion in the E200K form of hereditary prion disease.