How metal ions affect amyloid formation: Cu2+- and Zn2+-sensitive peptides.
The common feature of proteins involved in many neurodegenerative diseases is their ability to adopt at least two different stable conformations. The conformational transition that shifts the equilibrium from the functional, mostly partially alpha-helical structure, to the beta-sheet rich amyloid can be triggered by numerous factors, such as mutations in the primary structure or changes in the environment. We present a set of model peptides that, without changes in their primary structure, react in a predictable fashion in the presence of transition metal ions by adopting different conformations and aggregate morphologies. These de novo designed peptides strictly follow the characteristic heptad repeat of the alpha-helical coiled-coil structural motif. Furthermore, domains that favor beta-sheet formation have been incorporated to make the system prone to amyloid formation. As a third feature, histidine residues create sensitivity towards the presence of transition metal ions. CD spectroscopy, ThT fluorescence experiments, and transmission electron microscopy were used to characterize peptide conformation and aggregate morphology in the presence of Cu2+ and Zn2+. Furthermore, the binding geometry within peptide-Cu2+ complexes was characterized by electron paramagnetic resonance spectroscopy.
Pagel
Kevin
K
Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany.
Seri
Tomomi
T
von Berlepsch
Hans
H
Griebel
Jan
J
Kirmse
Reinhard
R
Böttcher
Christoph
C
Koksch
Beate
B
D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000187:drug effects / Q000648:ultrastructure; D002413:Cations, Divalent / Q000737:chemistry / Q000494:pharmacology; D002942:Circular Dichroism; D003300:Copper / Q000737:chemistry* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000187:drug effects; D012680:Sensitivity and Specificity; D015032:Zinc / Q000737:chemistry* / Q000494:pharmacology
D000682:Amyloid; D002413:Cations, Divalent; D010455:Peptides; D003300:Copper; D015032:Zinc