Human Molecular Genetics, Vol 8, 2107-2115, Copyright © 1999 by Oxford University Press
MJ Petris and JF Mercer
Menkes disease is an X-linked recessive copper deficiency disorder caused
by mutations in the ATP7A ( MNK ) gene which encodes a copper transporting
P-type ATPase (MNK). MNK is normally localized pre- dominantly in the trans
-Golgi network (TGN); however, when cells are exposed to excessive copper
it is rapidly relocalized to the plasma membrane where it functions in
copper efflux. In this study, the c-myc epitope was introduced within the
loop connecting the first and second transmembrane regions of MNK. This myc
epitope allowed detection of the protein at the surface of living cells and
provided the first experimental evidence supporting the common topological
model. In cells stably expressing the tagged MNK protein (MNK-tag),
extracellular antibodies were internalized to the perinuclear region,
indicating that MNK-tag at the TGN constitutively cycles via the plasma
membrane in basal copper conditions. Under elevated copper conditions,
MNK-tag was recruited to the plasma membrane; however, internalization of
MNK-tag was not inhibited and the protein continued to recycle through
cyto- plasmic membrane compartments. These findings suggest that copper
stimulates exocytic movement of MNK to the plasma membrane rather than
reducing MNK retrieval and indicate that MNK may remove copper from the
cytoplasm by transporting copper into the vesicles through which it cycles.
Newly internalized MNK-tag and transferrin were found to co- localize,
suggesting that MNK-tag follows a clathrin-coated pit/endosomal pathway
into cells. Mutation of the di-leucine, L1487 L1488, prevented uptake of
anti-myc antibodies in both basal and elevated copper conditions, thereby
identifying this sequence as an endocytic signal for MNK. Analysis of the
effects of the di-leucine mutation in elevated copper provided further
support for copper- stimulated exocytic movement of MNK from the TGN to the
plasma membrane.
ARTICLES
The menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal
The Murdoch Institute, Royal Children's Hospital, Parkville 3052, Australia, and.
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