Dynamics of Zn^II Binding as a Key Feature in the Formation of Amyloid Fibrils by Aβ11-28

Supramolecular assembly of peptides and proteins into amyloid fibrils is of multifold interest, going from materials science to physiopathology. The binding of metal ions to amyloidogenic peptides is associated with several amyloid diseases, and amyloids with incorporated metal ions are of interest in nanotechnology. Understanding the mechanisms of amyloid formation and the role of metal ions can improve strategies toward the prevention of this process and enable potential applications in nanotechnology. Here, studies on Zn^II binding to the amyloidogenic peptide Aβ11-28 are reported. Zn^II modulates the Aβ11-28 aggregation, in terms of kinetics and fibril structures. Structural studies suggest that Aβ11-28 binds Zn^II by amino acid residues Glu11 and His14 and that Zn^II is rapidly exchanged between peptides. Structural and aggregation data indicate that Zn^II binding induces the formation of the dimeric Zn^II₁(Aβ11-28)₂ species, which is the building block of fibrillar aggregates and explains why Zn^II binding accelerates Aβ11-28 aggregation. Moreover, transient Zn^II binding, even briefly, was enough to promote fibril formation, but the final structure resembled that of apo-Aβ11-28 amyloids. Also, seeding experiments, i.e., the addition of fibrillar Zn^II₁(Aβ11-28)₂ to the apo-Aβ11-28 peptide, induced aggregation but not propagation of the Zn^II₁(Aβ11-28)₂-type fibrils. This can be explained by the dynamic Zn^II binding between soluble and aggregated Aβ11-28. As a consequence, dynamic Zn^II binding has a strong impact on the aggregation behavior of the Aβ11-28 peptide and might be a relevant and so far little regarded parameter in other systems of metal ions and amyloidogenic peptides