The structure of complexes between zinc(ii) cations and histidine-rich repeats from the unstructured N-terminal domain of human prion protein

Abstract

Prion protein (PrP^C), a well-known protein pathogenic agent, consists of an ordered C-terminal domain and an unstructured N-terminal tail. The N-terminal region includes a highly conserved region consisting of four octarepeat sequences PHGGGWGQ (in short, octarepeats). These octarepeats are capable of binding metal ions such as Cu(II) and Zn(II). In this study, XAS and FTIR experiments revealed the specific stoichiometry and characteristic features of the Zn(II)-binding site in octarepeats. In the presence of Zn(II) ions, the octarepeat peptide can self-assemble and form fibrils. Although fully developed aggregates are visually distinct, their base PrP–Zn(II) complex geometry remains the same everywhere – Zn(II) is coordinated by N atoms from His residues in the octahedral structure, with axial water molecules being preferred. The coordination of Zn(II) ions promotes β-sheet formation in the secondary structure of the octarepeats, reducing the structural disorder level and favoring oligomerization in aqueous solutions—the results clearly evidence that Zn(II) ions have potential to promote neurodegenerative diseases via unwanted interactions with PrP.