Department of Macromolecular Physics, Faculty of Physics, Adam Mickiewicz University, 61-614, Poznań, Poland.
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106, Warszawa, Poland.
Sci Rep. 2021 Nov 4;11(1):21703. doi: 10.1038/s41598-021-00495-0.
The cellular prion protein (PrP) is a mainly α-helical 208-residue protein located in the pre- and postsynaptic membranes. For unknown reasons, PrP can undergo a structural transition into a toxic, β-sheet rich scrapie isoform (PrP) that is responsible for transmissible spongiform encephalopathies (TSEs). Metal ions seem to play an important role in the structural conversion. PrP 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 PrP and Zn(II) ions. Binding of a single Zn(II) ion to the PrP 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 PrP can bind Zn(II) under physiological conditions, these effects could be important for the physiological function of PrP.
细胞朊病毒蛋白（PrP）是一种主要由 208 个残基组成的 α-螺旋结构蛋白，位于突触前膜和突触后膜中。由于未知原因，PrP 可以发生结构转变，形成具有毒性的富含β-折叠的瘙痒症异构体（PrPsc），这种异构体负责可传播海绵状脑病（TSE）。金属离子似乎在结构转换中起着重要作用。PrP 结合锌（II）离子，可能参与金属离子转运和锌稳态。在这里，我们使用多种生物物理技术，包括光学和 NMR 光谱、分子动力学模拟和小角 X 射线散射，来表征人 PrP 与 Zn（II）离子之间的相互作用。通过八肽重复区的四个组氨酸残基，单个 Zn（II）离子与 PrP N 端结构域结合，诱导 C 端α-螺旋 2 和 3 发生结构转变，促进 N 端和 C 端结构域之间的相互作用，减小折叠蛋白的尺寸，并改变内部结构动力学。由于我们的结果表明 PrP 可以在生理条件下结合 Zn（II），这些影响可能对 PrP 的生理功能很重要。
