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

• Published in: The Journal of biological chemistry Vol. 275; no. 43; pp. 33650 - 33654
• Main Authors: Zhang, Y, Swietnicki, W, Zagorski, M G, Surewicz, W K, Sönnichsen, F D
• Format: Journal Article
• Language: English
• Published: United States 27.10.2000
• Subjects: Base Sequence; Creutzfeldt-Jakob Syndrome - genetics; Humans; Molecular Sequence Data; Mutation; Prions - chemistry; Protein Folding; Protein Structure, Secondary; PrP protein; Solutions; spongiform encephalopathy
• ISSN: 0021-9258
• DOI: 10.1074/jbc.C000483200

Prion propagation in transmissible spongiform encephalopathies involves the conversion of cellular prion protein, PrP(C), into a pathogenic conformer, PrP(Sc). Hereditary forms of the disease are linked to specific mutations in the gene coding for the prion protein. To gain insight into the molecular basis of these disorders, the solution structure of the familial Creutzfeldt-Jakob disease-related E200K variant of human prion protein was determined by multi-dimensional nuclear magnetic resonance spectroscopy. Remarkably, apart from minor differences in flexible regions, the backbone tertiary structure 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 the perturbation of surface electrostatic potential. The present structural data strongly suggest that protein surface defects leading to abnormalities in the interaction of prion protein with auxiliary proteins/chaperones or cellular membranes should be considered key determinants of a spontaneous PrP(C) --> PrP(Sc) conversion in the E200K form of hereditary prion disease.