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The molecular mechanism for human metallothionein-3 to protect against the neuronal cytotoxicity of Aβ1–42 with Cu ions

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Abstract

Aggregation and cytotoxicity of Aβ with redox-active metals in neuronal cells have been implicated in the progression of Alzheimer disease. Human metallothionein (MT) 3 is highly expressed in the normal human brain and is downregulated in Alzheimer disease. Zn7MT3 can protect against the neuronal toxicity of Aβ by preventing copper-mediated Aβ aggregation, abolishing the production of reactive oxygen species (ROS) and the related cellular toxicity. In this study, we intended to decipher the roles of single-domain proteins (α/β) and the α–β domain–domain interaction of Zn7MT3 to determine the molecular mechanism for protection against the neuronal cytotoxicity of Aβ1–42 with copper ions. With this in mind, the α and β single-domain proteins, heterozygous β(MT3)–α(MT1), and a linker-truncated mutant ∆31–34 were prepared and characterized. In the presence/absence of various Zn7MT3 proteins, the Aβ1–42–Cu2+-mediated aggregation, the production of ROS, and the cellular toxicity were investigated by transmission electron microscopy, ROS assay by means of a fluorescent probe, and SH-SY5Y cell viability, respectively. The β domain cannot abolish Aβ1–42–Cu2+-induced aggregation, and neither the β domain nor the α domain can quench the production of ROS because of the redox cycling of Aβ–Cu2+. Similarly to wild-type Zn7MT3, the heterozygous β(MT3)–α(MT1) possesses the characteristic of alleviating Aβ1–42 aggregation and oxidative stress to neuronal cells. Therefore, the two domains through the linker Lys-Lys-Ser form a cooperative unit, and each of them is indispensable in conducting its bioactivity. The α domain plays an important role in modulating the stability of the metal–thiolate cluster, and the α–β domain–domain interaction through the linker is critical for its protective role in the brain.

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Acknowledgments

This work was supported partly by the National Natural Science Foundation of China (no. 91013001, no. 20771029, and no. 31270869), Shanghai Pujiang Talent Project (08PJ14017), Shanghai Leading Academic Discipline Project (B108), the PhD Program of the Education Ministry of China (20100071110011), and the State Key Laboratory of Medical Neurobiology in the Shanghai Medical College of Fudan University, Shanghai, China.

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Correspondence to Xiangshi Tan.

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Luo, Y., Xu, Y., Bao, Q. et al. The molecular mechanism for human metallothionein-3 to protect against the neuronal cytotoxicity of Aβ1–42 with Cu ions. J Biol Inorg Chem 18, 39–47 (2013). https://doi.org/10.1007/s00775-012-0947-3

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  • DOI: https://doi.org/10.1007/s00775-012-0947-3

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