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.
Highlights
The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes
Circular dichroism (CD) spectroscopy was used to monitor changes in protein secondary structure induced by Zn(II) ions
Addition of twenty molar equivalents of Zn(II) to PrPC resulted in a general decrease in CD intensity over the whole wavelength range (Fig. 2A)
Summary
The cellular prion protein (PrPC) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. 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. It has been proposed that PrPC might have a significant role in the homeostasis of different metal ions[21,22], as the brain distribution of metal ions correlates with the PrPC expression level[23] It is still unclear if zinc dyshomeostasis, or metal imbalances in general, are part of the pathology in prion diseases, as appears to be the case in other neurodegenerative protein aggregation diseases such as Alzheimer’s 24
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