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J. Biol. Chem., Vol. 279, Issue 27, 27845-27848, July 2, 2004

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A Novel Role for the Immunophilin FKBP52 in Copper Transport^*

Reiko Sanokawa-Akakura, Huachang Dai, Shin Akakura, David Weinstein, J. Eduardo Fajardo¶, Steven E. Lang||, Scott Wadsworth||, John Siekierka||, and Raymond B. Birge**

From the Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, GliaMed, Inc., New York, New York 10032, ^¶The Rockefeller University, 1230 York Avenue, New York, New York 10021, and the ^||Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan, New Jersey 08869

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 ⁶⁴Cu-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.

Received for publication, March 19, 2004 , and in revised form, April 26, 2004.

^* This work was supported by a Johnson & Johnson-Research grant and Public Health Service Award NIHGM-55760 (to R. B. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence and reprint requests should be addressed: Dept. of Biochemistry and Molecular Biology, UMDNJ-New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103-6399. Tel.: 973-972-4497; Fax: 973-972-8601; E-mail: birgera{at}umdnj.edu.

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