Dynamics of ZnII 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 A beta 11-28 are reported. Zn-II modulates the A beta 11-28 aggregation, in terms of kinetics and fibril structures. Structural studies suggest that A beta 11-28 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-1(II)(A beta 11-28), species, which is the building block of fibrillar aggregates and explains why Zn-II binding accelerates A beta 11-28 aggregation. Moreover, transient Zn-II binding, even briefly, was enough to promote fibril formation, but the final structure resembled that of apo-A beta 11-28 amyloids. Also, seeding experiments, i.e., the addition of fibrillar Zn-1(II)(A beta 11-28), to the apo-A beta 11-28 peptide, induced aggregation but not propagation of the Zn-1(II)(A beta 11-28)(2)-type fibrils. This can be explained by the dynamic Zn-II binding between soluble and aggregated A beta 11-28. As a consequence, dynamic Zn-II binding has a strong impact on the aggregation behavior of the A beta 11-28 peptide and might be a relevant and so far little regarded parameter in other systems of metal ions and amyloidogenic peptides.