Selenoprotein P and selenoprotein M block Zn2+ -mediated Abeta42 aggregation and toxicity.

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Du X, Li H, Wang Z, Qiu S, Liu Q, Ni J

Selenoprotein P and selenoprotein M block Zn2+ -mediated Abeta42 aggregation and toxicity.

Metallomics. 2013 Jun;5(7):861-70. doi: 10.1039/c3mt20282h.

PubMed ID

23652332 [ View in PubMed

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Abstract

Aggregation and cytotoxicity of the amyloid-beta (Abeta) peptide with transition metal ions in neuronal cells have been suggested to be involved in the progression of Alzheimer's disease (AD). A therapeutic strategy to combat this incurable disease is to design chemical agents to target metal-Abeta species. Selenoproteins are a group of special proteins that contain the 21st amino acid Sec in their sequence. Due to the presence of Sec, studies of this group of proteins are basically focused on their roles in regulating redox potential and scavenging reactive oxygen species. Here, we reported that the His-rich domain of selenoprotein P (SelP-H) and the Sec-to-Cys mutant selenoprotein M (SelM') are capable of binding transition metal ions and modulating the Zn(2+)-mediated Abeta aggregation, ROS production and neurotoxicity. SelM' (U48C) and SelP-H were found to coordinate 0.5 and 2 molar equivalents of Zn(2+)/Cd(2+) with micromolar and submicromolar affinities, respectively. Metal binding induced the structural changes in SelP-H and SelM' according to the circular dichorism spectra. Zn(2+) binding to Abeta42 almost completely suppressed Abeta42 fibrillization, which could be significantly restored by SelP-H and SelM', as observed by thioflavin T (ThT) fluorescence and transmission electron microscopy (TEM). Interestingly, both SelP-H and SelM' inhibited Zn(2+)-Abeta42-induced neurotoxicity and the intracellular ROS production in living cells. These studies suggest that SelP and SelM may play certain roles in regulating redox balance as well as metal homeostasis.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Zinc chloride	Selenoprotein P	Protein	Humans	Unknown	Binder	Details
Zinc sulfate, unspecified form	Selenoprotein P	Protein	Humans	Unknown	Binder	Details