title: Selenoprotein P and selenoprotein M block Zn2+ -mediated Aβ42 aggregation and toxicity.
abstract: Aggregation and cytotoxicity of the amyloid-β (Aβ) 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-Aβ 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 Aβ 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 Aβ42 almost completely suppressed Aβ42 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+)-Aβ42-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.
authors: College of Life Sciences, Shenzhen Key Laboratory of Microbial Genetic Engineering, Shenzhen University, Shenzhen, China.
authors: Xiubo
authors: X
authors: Du
authors: Haiping
authors: H
authors: Li
authors: Zhi
authors: Z
authors: Wang
authors: Shi
authors: S
authors: Qiu
authors: Qiong
authors: Q
authors: Liu
authors: Jiazuan
authors: J
authors: Ni
mesh_terms: D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D001483:Base Sequence; D002942:Circular Dichroism; D017931:DNA Primers; D004926:Escherichia coli / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D051149:Selenoprotein P / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D051140:Selenoproteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D013056:Spectrophotometry, Ultraviolet; D015032:Zinc / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D017931:DNA Primers; C448999:SELM protein, human; D051149:Selenoprotein P; D051140:Selenoproteins; D015032:Zinc