Human Molecular Genetics, Vol 7, 1293-1300, Copyright © 1998 by Oxford University Press
S La Fontaine, SD Firth, PJ Lockhart, H Brooks, RG Parton, J Camakaris and JF Mercer
The Menkes protein (MNK or ATP7A) is an important component of the
mammalian copper transport pathway and is defective in Menkes disease, a
fatal X-linked disorder of copper transport. To study the structure and
function of this protein and to elucidate its role in cellular copper
homeostasis, a cDNA construct encoding the full-length MNK protein was
cloned into a mammalian expression vector under the control of the CMV
promoter. Transfection of this plasmid construct into CHO-K1 cells yielded
clones that expressed MNK at varying levels. Detailed characterization of
four clones showed that an increase in MNK protein expression led to a
corresponding increase in the level of copper resistance of the cells.
Subcellular localization studies showed that in the parental CHO-K1 and the
transfected cell lines, MNK was located in a post-Golgi compartment which,
based on immunogold electron microscopic analyses, most likely represented
the trans -Golgi network (TGN). When the extracellular copper concentration
was increased, MNK in the clones as well as in CHO-K1 cells was
redistributed to the cytoplasm and plasma membrane, but returned to the TGN
under basal, low copper conditions. This report presents the first
ultrastructural evidence for the association of MNK with vesicles within
the cell and with the TGN and plasma membrane. It also demonstrates the
stable expression of a functional MNK protein from a cDNA construct in
mammalian cells, as well as the copper-induced redistribution of MNK in a
cell line (CHO-K1) that was not selected for copper resistance or
overexpression of MNK.
ARTICLES
Functional analysis and intracellular localization of the human menkes protein (MNK) stably expressed from a cDNA construct in Chinese hamster ovary cells (CHO-K1)
The Murdoch Institute for Research into Birth Defects, Royal Children's Hospital, Parkville, Victoria 3052, Australia.
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