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Am J Physiol Cell Physiol (July 21, 2004). doi:10.1152/ajpcell.00179.2004
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Submitted on April 6, 2004
Accepted on July 13, 2004

Signals Regulating Trafficking of the Menkes (MNK ; ATP7A) Copper Translocating P-type ATPase in Polarized MDCK Cells

Mark A Greenough1, Luke B Pase1, Ilia Voskoboinik2, Michael J Petris3, Amy L Wilson-O'Brien1, and James Camakaris1*

1 Genetics, The University of Melbourne, Melbourne, Victoria, Australia
2 Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia
3 Biochemistry and Nutritional Sciences, University of Missouri, Columbia, Missouri, USA

* To whom correspondence should be addressed. E-mail: j.camakaris{at}unimelb.edu.au.

The Menkes protein (MNK; ATP7A) functions as a transmembrane copper translocating P-type ATPase and plays a vital role in systemic copper absorption in the gut and copper reabsorption in the kidney. Polarized epithelial cells such as Madin-Darby canine kidney (MDCK) cells are a physiologically relevant model for systemic copper absorption and reabsorption in vivo. In this study, cultured MDCK cells were used to characterize MNK trafficking and enabled the identification of signaling motifs required to target the protein to specific membranes. Using confocal laser scanning microscopy (CLSM) and surface biotinylation we demonstrate that MNK relocalizes from the Golgi to the basolateral (BL) membrane under elevated copper conditions. As previously shown in non-polarized cells, the metal binding sites in the N-terminal domain of MNK were found to be required for copper-regulated trafficking from the Golgi to the PM. These data provide molecular evidence that is consistent with the presumed role of this protein in systemic copper absorption in the gut and reabsorption in the kidney. Using site-directed mutagenesis, we identified a di-leucine motif proximal to the C-terminus of MNK that was critical for correctly targeting the protein to the BL membrane, and a putative PDZ target motif that was required for localization at the BL membrane in elevated copper.




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