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The molecular mechanism for human metallothionein-3 to protect against the neuronal cytotoxicity of Aβ1–42 with Cu ions
- Source :
- JBIC Journal of Biological Inorganic Chemistry. 18:39-47
- Publication Year :
- 2012
- Publisher :
- Springer Science and Business Media LLC, 2012.
-
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. Zn(7)MT3 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 Zn(7)MT3 to determine the molecular mechanism for protection against the neuronal cytotoxicity of Aβ(1-42) 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 Zn(7)MT3 proteins, the Aβ(1-42)-Cu(2+)-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 Aβ(1-42)-Cu(2+)-induced aggregation, and neither the β domain nor the α domain can quench the production of ROS because of the redox cycling of Aβ-Cu(2+). Similarly to wild-type Zn(7)MT3, the heterozygous β(MT3)-α(MT1) possesses the characteristic of alleviating Aβ(1-42) 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.
- Subjects :
- Cell Survival
Mutant
Nerve Tissue Proteins
medicine.disease_cause
Biochemistry
Inorganic Chemistry
Protein structure
Cell Line, Tumor
medicine
Humans
Metallothionein
Viability assay
Protein Structure, Quaternary
Cytotoxicity
Neurons
chemistry.chemical_classification
Reactive oxygen species
Amyloid beta-Peptides
Chemistry
Metallothionein 3
Peptide Fragments
Protein Structure, Tertiary
Cell biology
Cell culture
Protein Multimerization
Reactive Oxygen Species
Copper
Oxidative stress
Subjects
Details
- ISSN :
- 14321327 and 09498257
- Volume :
- 18
- Database :
- OpenAIRE
- Journal :
- JBIC Journal of Biological Inorganic Chemistry
- Accession number :
- edsair.doi.dedup.....ff5b9795b0be90ede34b54caa4491d90