How Metal Ions Affect Amyloid Formation: Cu²⁺‐ and Zn²⁺‐Sensitive Peptides

Abstract

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.

Calcium Ions to Remotely Control the Reversible Switching of Secondary and Quaternary Structures in Bioconjugates

“…[25][26][27] Herein we report on a novel regulative mechanism for reversibly controlling the function of a peptide aggregator domain in peptide-polymer conjugates using calcium ions. While Ca 2+ was previously used to cross-link preformed peptide fibrils, [28] the presented strategy involves control at the molecular peptide level.…”

Effects of Zn2+ Binding on the Structural and Dynamic Properties of Amyloid Β Peptide Associated with Alzheimer’s Disease: Asp1 or Glu11?

“…57,58 The entropy of Aβ42 has been estimated to be 859.6 kcal/mol based on the 3D-RISM calculations, 57 thus, the entropy loss of Aβ40 (assumed the same as Aβ42, and taken as a reference) is much Figure 10 and Supporting Information Figure S6 22,62,63 resulting in heterogeneous distribution of binding conformations. 7,8,64 In addition, the binding mode is also dependent on the length of Aβ peptide. 22 Note that the fragment of 1−16 of Aβ (Aβ16) has been considered as the metal binding domain.…”

Intramolecular Charge Interactions as a Tool to Control the Coiled‐Coil‐to‐Amyloid Transformation

“…The sensitivity towards metal ions was realized by incorporation of two histidine residues at different positions within the coiled coil. [18] In contrast, sensitivity to the pH value was achieved by an accumulation of positively charged lysine residues at one side of the helical cylinder. [19] Protonation of these residues at acidic pH values results in the formation of an excessively charged domain, which induces an association into amyloidlike structures, whereas non-amyloidogenic coiled-coil assemblies have been obtained under neutral conditions.…”

“…In these systems either the presence of metal ions [18] or changes in concentration and pH value [19] were shown to trigger conformational transitions in either direction. The sensitivity towards metal ions was realized by incorporation of two histidine residues at different positions within the coiled coil.…”