Menkes

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Research

Copper plays a crucial role in the body as it's needed as a co-factor for copper dependent enzymes (cuproenzymes) to function. For example the cuproenzyme tyrosinase which is involved in melanin synthesis for skin pigmentation.   

The ATP7A and ATP7B genes, which encode the Menkes and Wilson disease proteins (MNK and WND respectively), are P-type ATPases that act as copper transporters, linking cation transport to ATP hydrolysis to pump copper across cell membranes. These transporters have a key part to play in regulating copper levels in the body.

The WND protein is expressed primarily in the liver, but also to a lesser extent in the brain, kidney, heart and lungs. MNK protein is expressed ubiquitously in non-hepatic tissues. Under normal physiological conditions MNK and WND reside predominantly in the Trans-Golgi network (TGN) of cells where they provide cuproenzymes traversing the secretory pathway with copper. Under these conditions a minority of MNK and WND cycles between the TGN and the plasma membrane/vesicles close to the cell surface. Although Copper is an essential element in the body it is only needed in small amounts and too much is toxic. When copper levels rise MNK and WND play a defensive role by trafficking en-masse to the cell periphery to efflux copper from the cell, returning to the TGN when copper levels are reduced.

Our group has focused on deciphering the molecular mechanisms that govern the movement of MNK out of the TGN to the cell surface (exocytosis) and regulate its return back to the TGN (endocytosis). To read further about our discoveries please see our publications.

   

MNK2

The figure above shows that MNK traffics to and from the cell surface in response to copper levels. Left panel: at steady state (low copper) MNK (green) resides in the TGN compartment, demonstrated by its colocalisation with the TGN marker TGN46 (red). The overlapping staining pattern of the two proteins appears in yellow. Middle panel: when copper levels are elevated MNK traffics to the cells surface. Right panel: MNK returns to the TGN when copper is washed out of the cell.