Copper stimulates trafficking of a distinct pool of the Menkes copper ATPase (ATP7A) to the plasma membrane and diverts it into a rapid recycling pool.
MNK (Menkes copper-translocating P-type ATPase, or the Menkes protein; ATP7A) plays a key role in regulating copper homoeostasis in humans. MNK has been shown to have a dual role in the cell: it delivers copper to cuproenzymes in the Golgi compartment and effluxes excess copper from the cell. These roles can be achieved through copper-regulated trafficking of MNK. It has previously been shown to undergo trafficking from the trans -Golgi network to the plasma membrane in response to elevated copper concentrations, and to be endocytosed from the plasma membrane to the trans -Golgi network upon the removal of elevated copper. However, the fundamental question as to whether copper influences trafficking of MNK to or from the plasma membrane remained unanswered. In this study we utilized various methods of cell-surface biotinylation to attempt to resolve this issue. These studies suggest that copper induces trafficking of MNK to the plasma membrane but does not affect its rate of internalization from the plasma membrane. We also found that only a specific pool of MNK can traffic to the plasma membrane in response to elevated copper. Significantly, copper appeared to divert MNK into a fast-recycling pool and prevented it from recycling to the Golgi compartment, thus maintaining a high level of MNK in the proximity of the plasma membrane. These findings shed new light on the cell biology of MNK and the mechanism of copper homoeostasis in general.
Pase
Luke
L
Department of Genetics, University of Melbourne, Melbourne, VIC 3010, Australia.
Voskoboinik
Ilia
I
Greenough
Mark
M
Camakaris
James
J
D000251:Adenosine Triphosphatases / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D027682:Cation Transport Proteins / Q000378:metabolism* / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D003300:Copper / Q000494:pharmacology*; D006224:Cricetinae; D004705:Endocytosis / Q000187:drug effects; D007700:Kinetics; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000502:physiology
D027682:Cation Transport Proteins; D011993:Recombinant Fusion Proteins; D003300:Copper; D000251:Adenosine Triphosphatases