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.