Zn(II) binding causes interdomain changes in the structure and flexibility of the human prion protein

Abstract

The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrPC can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrPSc) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrPC binds Zn(II) ions and may be involved in metal ion transport and zinc homeostasis. Here, we use multiple biophysical techniques including optical and NMR spectroscopy, molecular dynamics simulations, and small angle X-ray scattering to characterize interactions between human PrPC and Zn(II) ions. Binding of a single Zn(II) ion to the PrPC N-terminal domain via four His residues from the octarepeat region induces a structural transition in the C-terminal α-helices 2 and 3, promotes interaction between the N-terminal and C-terminal domains, reduces the folded protein size, and modifies the internal structural dynamics. As our results suggest that PrPC can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrPC.

Metals in ALS TDP-43 Pathology

“…Later, a Zn-binding site in the RRM2 domain has been described, likely involving the negatively charged glutamate E261 and the two histidines H256 and H264 [130]. Similar results have been observed for the binding of Zn ions to histidine residues in PrP [141,142]. However, binding of a single Zn ion to the Aβ peptide involved in AD, mainly via histidines, promoted disordered aggregation and retarded formation of regular amyloid fibrils [61,143,144].…”

A tetracationic porphyrin with dual anti-prion activity

“… 4 Cu(II) and Zn(II) promote tertiary contacts between the N- and C-terminal PrP C domains. 5 , 6 , 7 , 8 …”

Prion Protein Octarepeat Domain Forms Transient β-Sheet Structures upon Residue-Specific Binding to Cu(II) and Zn(II) Ions

“…Thus, it is possible that only high concentrations of metal ionsmore than a 1:1 ratiowould induce secondary structures suitable for amyloid formation. In such cases, the TSE diseases might be a result of altered Cu­(II) or Zn­(II) homeostasis. ,, On the other hand, the binding of divalent metal ions to full-length PrP C is known to induce interactions between the metal-bound OR region and the C-terminal helical domain. ,, Such interactions likely help to hold the protein structure together, and it is generally known that structured proteins must first unfold before they can misfold into β-sheet structures (or β-sheet hairpins) and begin to assemble into amyloid forms. In a PrP C variant with point mutations corresponding to genetic Creutzfeldt–Jakob disease, fatal familial insomnia, and the Gerstmann–Sträussler–Scheinker disease, the addition of Zn­(II) ions induced broadening of NMR peaks indicative of weaker interactions between the Zn­(II)-bound OR region and the C-terminal domain than in the native protein.…”

“… Top: sequence of the human prion protein, with the octarepeat region marked in orange, β-sheets marked in green, and α-helices marked in blue. The image is from Gielnik et al 28 under a CC BY 4.0 license. Bottom: the octarepeat (OR) region studied in this paper comprises residues 58–93 of the prion protein, i.e., PrP C (58–93).…”