Inhibitory effect of selenoprotein P on Cu(+)/Cu(2+)-induced Aβ42 aggregation and toxicity.
It has been suggested that the aggregation and cytotoxicity of amyloid-β (Aβ) peptide with transition-metal ions in neuronal cells is involved in the progression of Alzheimer's disease (AD). Selenoproteins are a group of special proteins that contain the 21st amino acid selenocysteine in their sequence, and they are found to be involved in the onset and progression of AD. Here, we report that the histidine-rich domain of selenoprotein P (SelP-H) is capable of binding Cu ions in both oxidation states of Cu(+) and Cu(2+) with high affinity and of modulating Cu(+) and Cu(2+)-mediated Aβ aggregation, reactive oxygen species (ROS) production, and neurotoxicity. SelP-H was found to coordinate 1 and 2 mol equiv of Cu(+) and Cu(2+) with sub-picomolar and nanomolar affinities, respectively. Cu(+)/Cu(2+) binding to Aβ42 inhibited the fibrillization of Aβ42 but induced it to form amorphous aggregates, which could be significantly restored by SelP-H, as observed by thioflavin T fluorescence and transmission electron microscopy. Interestingly, SelP-H inhibited Cu(+)/Cu(2+)-Aβ42-induced neurotoxicity and the intracellular ROS production in living cells. These studies suggest that SelP may play certain roles in regulating redox balance as well as metal homeostasis.
Department of Marine Biology, Shenzhen Key Laboratory of Marine Biotechnology and Ecology, Shenzhen University , Shenzhen 518060, China.
Xiubo
X
Du
Zhi
Z
Wang
Youbiao
Y
Zheng
Haiping
H
Li
Jiazuan
J
Ni
Qiong
Q
Liu
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D002460:Cell Line; D003300:Copper / Q000378:metabolism*; D006639:Histidine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism* / Q000648:ultrastructure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism; D051149:Selenoprotein P / Q000737:chemistry* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D051149:Selenoprotein P; C075222:amyloid beta-protein (1-42); D006639:Histidine; D003300:Copper