A Novel Role for the Immunophilin FKBP52 in Copper Transport

A Novel Role for the Immunophilin FKBP52 in Copper Transport

FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans -isomerase (PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration a...

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Published in:The Journal of biological chemistry Vol. 279; no. 27; pp. 27845 - 27848
Main Authors: Sanokawa-Akakura, Reiko, Dai, Huachang, Akakura, Shin, Weinstein, David, Fajardo, J Eduardo, Lang, Steven E, Wadsworth, Scott, Siekierka, John, Birge, Raymond B
Format: Journal Article
Language:English
Published: United States American Society for Biochemistry and Molecular Biology 02-07-2004
Subjects:
Animals
Biological Transport
Blotting, Western
Calcium - metabolism
Cell Line
Cell Survival
Chelating Agents - pharmacology
Copper - metabolism
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Gene Library
Genetic Vectors
Glutathione Transferase - metabolism
Humans
Immunophilins - metabolism
Kinetics
Models, Genetic
Neurons - metabolism
Phenanthrolines - pharmacology
Precipitin Tests
Protein Structure, Tertiary
Rats
Tacrolimus Binding Proteins - physiology
Time Factors
Two-Hybrid System Techniques
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Summary:FK506-binding protein 52 (FKBP52) is an immunophilin that possesses peptidylprolyl cis/trans -isomerase (PPIase) activity and is a component of a subclass of steroid hormone receptor complexes. Several recent studies indicate that immunophilins can regulate neuronal survival and nerve regeneration although the molecular mechanisms are poorly understood. To investigate the function of FKBP52 in the nervous system, we employed a yeast two-hybrid strategy using the PPIase domain (domain I) as bait to screen a neonatal rat dorsal root ganglia cDNA expression library. We identified an interaction between FKBP52 domain I and Atox1, a copper-binding metallochaperone. Atox1 interacts with Menkes disease protein and Wilson disease protein (WD) and functions in copper efflux. The interaction between FKBP52 and Atox1 was observed in both glutathione S -transferase pull-down experiments and when proteins were ectopically expressed in human embryonic kidney (HEK) 293T cells and was sensitive to FK506. Interestingly, the FKBP52/Atox1 interaction was enhanced when HEK 293T cells were cultured in copper-supplemented medium and decreased in the presence of the copper chelator, bathocuproine disulfate, suggesting that the interaction is regulated in part by intracellular copper. Overexpression of FKBP52 increased rapid copper efflux in 64 Cu-loaded cells, as did the overexpression of WD transporter. Taken together, our present findings suggest that FKBP52 is a component of the copper efflux machinery, and in so, may also promote neuroprotection from copper toxicity.
Bibliography:ObjectType-Article-2
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.C400118200