NR APJC
AU Kuwata,K.; Matumoto,T.; Cheng,H.; Nagayama,K.; James,T.L.; Roder,H.
TI NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126
QU Proceedings of the National Academy of Sciences of the United States of America 2003 Dec 9; 100(25): 14790-5
PT journal article
AB PrP106-126, a peptide corresponding to residues 107-127 of the human prion protein, induces neuronal cell death by apoptosis and causes proliferation and hypertrophy of glia, reproducing the main neuropathological features of prion-related transmissible spongiform encephalopathies, such as bovine spongiform encephalopathy and Creutzfeldt-Jakob disease. Although PrP106-126 has been shown to form amyloid-like fibrils in vitro, their structural properties have not been elucidated. Here, we investigate the conformational characteristics of a fibril-forming fragment of the mouse prion protein, MoPrP106-126, by using electron microscopy, CD spectroscopy, NMR-detected hydrogen-deuterium exchange measurements, and molecular dynamics simulations. The fibrils contain approximately 50% beta-sheet structure, and strong amide exchange protection is limited to the central portion of the peptide spanning the palindromic sequence VAGAAAAGAV. Molecular dynamics simulations indicate that MoPrP106-126 in water assumes a stable structure consisting of two four-stranded parallel beta-sheets that are tightly packed against each other by methyl-methyl interactions. Fibril formation involving polyalanine stacking is consistent with the experimental observations.
MH Animals; Circular Dichroism; Hydrogen/*chemistry; Magnetic Resonance Spectroscopy; Mice; Microscopy, Electron; Models, Molecular; Neurons/metabolism; Peptide Fragments/*chemistry; Peptides/chemistry; Prions/*chemistry; Protein Conformation; Protein Structure, Secondary; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
AD *Department of Biochemistry and Biophysics, School of Medicine, Gifu University, 40 Tsukasa-machi, Gifu 500-8705, Japan; ()Laboratory of Ultrastructure Research, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585, Japan; ()Basic Science Division, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111; ( paragraph sign )Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143.
SP englisch
PO USA