The conformational conversion of prion protein (PrP) from an alpha-helix-rich normal cellular isoform (PrPC) to a beta-sheet-rich pathogenic isoform (PrPSc) is a key event in the development of prion diseases, and it takes place in caveolae, cavelike invaginations of the plasma membrane. A peptide homologous to residues 106-126 of human PrP (PrP106-126) is known to share several properties with PrPSc, e.g., the capability to form a beta-sheet and toxicity against PrPC-expressing cells. PrP106-126 is thus expected to represent a segment of PrP that is involved in the formation of PrPSc. We have examined the effect of lipid membranes containing negatively charged ganglioside, an important component of caveolae, on the secondary structure of PrP106-126 by circular dichroism. The peptide forms an alpha-helical or a beta-sheet structure on the ganglioside-containing membranes. The beta-sheet content increases with an increase of the peptide:lipid ratio, indicating that the beta-sheet formation is linked with self-association of the positively charged peptide on the negatively charged membrane surface. Analogous beta-sheet formation is also induced by membranes composed of negatively charged and neutral glycerophospholipids with high and low melting temperatures, respectively, in which lateral phase separation and clustering of negatively charged lipids occur as shown by Raman spectroscopy. Since ganglioside-containing membranes also exhibit lateral phase separation, clustered negative charges are concluded to be responsible for the beta-sheet formation of PrP106-126. In caveolae, clustered ganglioside molecules are likely to interact with the residue 106-126 region of PrPC to promote the PrPC-to-PrPSc conversion.
As the maximal K+-conductance (or K+-channel density) of the Hodgkin-Huxley equations is reduced, the stable resting membrane potential bifurcates at a subcritical Hopf bifurcation into small amplitude unstable oscillations. These small amplitude solutions jump to large amplitude periodic solutions that correspond to a repetitive discharge of action potentials. Thus the specific channel density can act as a bifurcation parameter, and can control the excitability and autorhythmicity of excitable membranes.
Conformational transition of monomeric amyloid b-peptide (Ab) to a self-associated b-sheet structure is considered to be an initial step in the development of Alzheimer's disease. Several lines of evidence suggest that physiologically abundant lipid membranes and metal ions are involved in this step. We have demonstrated that Ab binds to the phosphatidylcholine membrane in the lamellar gel phase but not in the liquid crystalline phase by using ‰uorescence and circular dichroism spectroscopy. The membrane-bound Ab molecule takes a-helical or b-sheet structure depending on the temperature. Tightly packed phosphatidylcholine membranes appear to serve as a platform for non-electrostatic binding and self-association of Ab. We have also examined Zn(II) and Cu(II) binding modes of Ab by Raman spectroscopy. The Raman spectra demonstrate that three histidine residues in the N-terminal region of Ab provide primary metal binding sites. Zn(II) binds to the N t atom of histidine and the peptide aggregates through intermolecular His-Zn-His bridges. In contrast, Cu(II) ion is chelated by the N p atom of histidine and deprotonated main-chain amide nitrogens to form a soluble complex. Ourˆndings on the conformational regulation of Ab may help in better understanding the molecular basis for the development of Alzheimer's disease.
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