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

TL;DR

This study explores how zinc ions bind to a specific region of the prion protein, potentially contributing to neurodegenerative diseases.

Contribution

The study reveals the specific coordination geometry of Zn(ii) ions with histidine residues in prion protein octarepeats.

Findings

Zn(ii) ions are coordinated by histidine residues in an octahedral geometry with axial water molecules.

Zn(ii) binding promotes β-sheet formation and oligomerization of the prion protein octarepeats.

Zn(ii) coordination reduces structural disorder and may contribute to neurodegenerative diseases.

Abstract

Prion protein (PrPC), 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.

Prion protein (PrPC), a well-known protein pathogenic agent, consists of an ordered C-terminal domain and an unstructured N-terminal tail. EXAFS shows it coordinates Zn2+ in octahedral geometry with four His groups involved.

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