Human Molecular Genetics, Vol 7, 2063-2071, Copyright © 1998 by Oxford University Press
MJ Petris, J Camakaris, M Greenough, S LaFontaine and JFB Mercer
The human X-linked recessive disorder of copper metabolism, Menkes disease,
is caused by a defect in the MNK ( ATP7A ) gene which encodes a
transmembrane copper-transporting P-type ATPase (MNK). MNK is an important
component of the mammalian copper transport pathway, and previous studies
in cultured cells have localized MNK to the final compartment of the Golgi
apparatus, the trans -Golgi network (TGN). At this location, MNK is
predicted to supply copper to copper-dependent enzymes as they migrate
through the secretory pathway. However, under conditions of elevated
extracellular copper, the MNK protein undergoes a rapid relocalization to
the plasma membrane where it functions in the efflux of copper from cells.
In this study, three di-leucine motifs and a cluster of four acidic amino
acids within the C-terminal region of MNK were investigated as candidate
signals necessary for steady-state TGN localization. In vitro mutagenesis
of the human MNK cDNA and immunofluorescence detection of mutant forms of
MNK expressed in cultured cells demonstrated that the di-leucine,
L1487L1488, was essential for localization of MNK within the TGN, but not
for copper efflux. We suggest that this di-leucine motif is a putative
endocytic targeting motif necessary for the retrieval of MNK from the
plasma membrane to the TGN. Our data, along with the recent demonstration
that the third transmembrane region of MNK functions as a TGN targeting
signal, suggests that MNK localization to the TGN may be a two-step process
involving TGN retention via the transmembrane region, and recycling to this
compartment from the plasma membrane via the L1487L1488 motif.
ARTICLES
A C-terminal di-leucine is required for localization of the Menkes protein in the trans-Golgi network
The Murdoch Institute, Royal Children's Hospital and Department of Genetics, University of Melbourne, Parkville 3052, Australia.
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