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The multi-layered regulation of copper translocating P-type ATPases

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Abstract

The copper-translocating Menkes (ATP7A, MNK protein) and Wilson (ATP7B, WND protein) P-type ATPases are pivotal for copper (Cu) homeostasis, functioning in the biosynthetic incorporation of Cu into copper-dependent enzymes of the secretory pathway, Cu detoxification via Cu efflux, and specialized roles such as systemic Cu absorption (MNK) and Cu excretion (WND). Essential to these functions is their Cu and hormone-responsive distribution between the trans-Golgi network (TGN) and exocytic vesicles located at or proximal to the apical (WND) or basolateral (MNK) cell surface. Intriguingly, MNK and WND Cu-ATPases expressed in the same tissues perform distinct yet complementary roles. While intramolecular differences may specify their distinct roles, cellular signaling components are predicted to be critical for both differences and synergy between these enzymes. This review focuses on these mechanisms, including the cell signaling pathways that influence trafficking and bi-functionality of Cu-ATPases. Phosphorylation events are hypothesized to play a central role in Cu homeostasis, promoting multi-layered regulation and cross-talk between cuproenzymes and Cu-independent mechanisms.

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Acknowledgments

The authors are supported by a NHMRC project grant (JC) and J.C. Rowden White Trust equipment grant and Melbourne Research Scholarship (postgraduate scholarship for N.V.). R.B.P is supported by a NHMRC Senior Research Fellowship. K.G. is supported by a J. N. Peter’s Bequest Fellowship. We appreciate the contributions of Professor Enrique Rodriguez-Boulan and Dr Ami Deora of Weill Cornell Medical College, NY, USA, for collaborative research and discussions on copper-ATPases in RPE cells.

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Veldhuis, N.A., Gaeth, A.P., Pearson, R.B. et al. The multi-layered regulation of copper translocating P-type ATPases. Biometals 22, 177–190 (2009). https://doi.org/10.1007/s10534-008-9183-2

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