Conformational pH dependence of intermediate states during oligomerization of the human prion protein
- 1 March 2008
- journal article
- Published by Wiley in Protein Science
- Vol. 17 (3), 537-544
- https://doi.org/10.1110/ps.073163308
Abstract
Intermediate states are key to understanding the molecular mechanisms governing protein misfolding. The human prion protein (PrP) can follow various misfolding pathways, and forms a soluble beta-sheet-rich oligomer under acidic, mildly denaturing, high salt conditions. Here we describe a fast conformational switch from the native alpha-monomer to monomeric intermediate states under oligomer-forming conditions, followed by a slower oligomerization process. We observe a pH dependence of the secondary structure of these intermediate forms, with almost native-like alpha-helical secondary structure at pH 4.1 and predominantly beta-sheet characteristics at pH 3.6. NMR spectroscopy differentiates these intermediate states from the native protein and indicates dynamic rearrangements of secondary structure elements characteristic of a molten globule. The alpha-helical intermediate formed at pH 4.1 can convert to the beta-sheet conformation at pH 3.6 but not vice versa, and neither state can be reconverted to an alpha-monomer. The presence of methionine rather than valine at codon 129 accelerates the rate of oligomer formation from the intermediate state.Keywords
This publication has 43 references indexed in Scilit:
- NMR characterization of the pH 4 β-intermediate of the prion protein: the N-terminal half of the protein remains unstructured and retains a high degree of flexibilityBiochemical Journal, 2006
- Early Intermediate in Human Prion Protein Folding As Evidenced by Ultrarapid Mixing ExperimentsJournal of the American Chemical Society, 2006
- The presence of valine at residue 129 in human prion protein accelerates amyloid formationFEBS Letters, 2005
- Rapid formation of amyloid from α‐monomeric recombinant human PrP in vitroProtein Science, 2005
- Synthetic Mammalian PrionsScience, 2004
- The Residue 129 Polymorphism in Human Prion Protein Does Not Confer Susceptibility to Creutzfeldt-Jakob Disease by Altering the Structure or Global Stability of PrPCPublished by Elsevier ,2004
- Identification and characterization of key kinetic intermediates in amyloid β-protein fibrillogenesis11Edited by F. CohenJournal of Molecular Biology, 2001
- The Role of Disulfide Bridge in the Folding and Stability of the Recombinant Human Prion ProteinJournal of Biological Chemistry, 2001
- NMRPipe: A multidimensional spectral processing system based on UNIX pipesJournal of Biomolecular NMR, 1995
- Novel Proteinaceous Infectious Particles Cause ScrapieScience, 1982