The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes
作者:, M. K. Mathew
摘要:Abstract Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrPSc) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Sträussler-Scheinker syndrome, but no accumulation of PrPSc is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K+, and forms K+- and Ca2+-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that upon interaction with lipid, the central hydrophobic region (109–132) of the protein is protected against exchange, making it a good candidate for inserting into the membrane and lining the channel. HDX-MS also shows a dramatic increase in the protein-lipid stoichiometry for A116V moPrP, providing a rationale for its increased channel-forming capability. The results suggest that ion channel formation may be a possible mechanism of PrP-mediated neurodegeneration by the transmembrane forms of PrP.
关键词:
论文方向:细胞生物学,生物物理学[{"id":13,"name":"细胞生物学"},{"id":19,"name":"生物物理学"}] 发表期刊:Biophysical Journal Volume 110, Issue 8
发表时间:Tue Apr 26 00:00:00 CST 2016
数字识别码:10.1016/j.bpj.2016.03.017
是否作者本人: 否
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