NMR-detected hydrogen exchange and molecular dynamics simulations provide structural insight into fibril formation of prion protein fragment 106-126.
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.
Kuwata
Kazuo
K
Department of Biochemistry and Biophysics, School of Medicine, Gifu University, 40 Tsukasa-machi, Gifu 500-8705, Japan. kuwata@cc.gifu-u.ac.jp
Matumoto
Tomoharu
T
Cheng
Hong
H
Nagayama
Kuniaki
K
James
Thomas L
TL
Roder
Heinrich
H
D000818:Animals; D002942:Circular Dichroism; D006859:Hydrogen / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008854:Microscopy, Electron; D008958:Models, Molecular; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D011328:Prions / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary
D010446:Peptide Fragments; D010455:Peptides; D011328:Prions; C082632:prion protein (106-126); D006859:Hydrogen