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Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, MI 48109-0606
2To whom correspondence should be addressed
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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KEY WORDS: • copper • transport • distribution • Menkes • Wilson's disease • homeostatic regulation
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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). What is so
special about this trace element that makes it essential in biology?
Copper ions undergo unique chemistry due to their ability to adopt
distinct redox states, either oxidized [Cu(II)] or in the reduced
state [Cu(I)]. Consequently, Cu ions serve as important catalytic
cofactors in redox chemistry for proteins that carry out fundamental
biological functions that are required for growth and development. As
shown in Table 1
, Cu requiring proteins are involved in a variety of biological
processes and deficiency in these enzymes, or alterations in their
activities, often cause disease states or pathophysiological
conditions. The dietary intake of Cu by humans has been estimated to
range from 0.6–1.6 mg Cu per day (Linder and Hazegh-Azam 1996
), through the ingestion of food sources rich in Cu such as
legumes, beef and shellfish. The Cu that is ingested is readily
absorbed and distributed to copper-requiring proteins with
apparently little storage of excess Cu in the body.
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). Hydroxyl
radicals are believed to be responsible for devastating cellular damage
that includes lipid peroxidation in membranes, direct oxidation of
proteins, and cleavage of DNA and RNA molecules. Indeed, the generation
and action of ROS are thought to be major contributing factors to the
development of cancer, diseases of the nervous system and aging
(Halliwell and Gutteridge 1990
). In addition to the
generation of ROS, Cu may manifest its toxicity by displacing other
metal cofactors from their natural ligands in key cellular signaling
proteins. For example, the replacement of Zn(II) by
Cu(II) in the zinc-finger DNA binding domain of the human
estrogen receptor renders this protein defective in binding to its
cognate target DNA sequences in vitro, thereby potentially interfering
with its role in hormone-dependent signal transduction in vivo
(Predki and Sarkar 1992
). It is highly likely that Cu is
able to displace metal ions in a number of catalytic or structural
motifs in many cellular proteins. Given that Cu is both essential and
toxic, organisms must implement uptake mechanisms to extract Cu from
nutrients, transport Cu across biological membranes and deliver it to
Cu-requiring proteins. Furthermore, precise regulatory mechanisms
must be in place to prevent the accumulation of Cu ions to toxic
levels. The importance of maintaining this critical balance is
underscored by the existence of two well-characterized human
genetic diseases in Cu transport, Menkes and Wilson's diseases
(Bull and Cox 1994
, Bull et al. 1993
,
Chelly et al. 1993
, Mercer et al. 1993
,
Vulpe et al. 1993
, Yamaguchi et al. 1993
). The identification of the human genes that are defective
in these, and perhaps other Cu metabolic diseases, and the
characterization of their gene products will greatly enhanced our
understanding of Cu ion homeostasis in general.
Maintaining appropriate Cu homeostasis demands a critical orchestration
between Cu uptake and distribution within cells, and detoxification and
removal. In this review, we focus on very recent advances in the
molecular mechanisms of Cu uptake into and its distribution within
cells as well as its distribution to different tissues in the context
of the whole organism. We also discuss the modes by which these steps
are regulated in order to ensure that sufficient Cu is available to
drive essential biochemical processes while preventing its accumulation
to toxic levels. The reader is referred to several excellent recent
reviews which emphasize different aspects of Cu metabolism including Cu
detoxification (Koch et al. 1997
, Winge 1998
, Winge et al. 1998
), Cu coordination
chemistry (Koch et al. 1997
), cellular Cu transport
(Eide 1998
, Radisky and Kaplan 1999
,
Vulpe and Packman 1995
), nutrition (Linder and Hazegh-Azam 1996
), links with iron transport
(Askwith and Kaplan 1998
, Winzerling and Law 1997
), and Menkes and Wilson's diseases (Bull and Cox 1994
, DiDonato and Sarkar 1997
).
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Copper uptake and absorption |
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TOPABSTRACTINTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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Initial insight into the identification of cellular components that play key roles in Cu ion homeostasis, as for many cellular processes, was derived from studies in model systems such as bacteria and yeast. Although not necessarily entirely conserved in their mechanisms between species, a striking observation is that proteins involved in Cu ion transport share what may be considered modular functional domains. The identification of Cu transport proteins in model systems has often lead to the discovery of their mammalian homologues, or mechanistic insight into how these proteins function overall in Cu ion transport.
Recent investigations into Cu uptake in the gram-positive
bacterium, Enterococcus hirae, have provided an excellent
fundamental description of this process. In E. hirae, an
operon containing five genes, copX, Y, Z, A and B, plays an
important role in Cu ion homeostasis (Odermatt et al. 1992
, Solioz et al. 1994
). The CopA and CopB
proteins are two integral membrane P-type ATPases that are
necessary for the transport of Cu into cells under Cu limiting
conditions, and Cu efflux under conditions of high Cu ion levels,
respectively (Odermatt et al. 1993
, Odermatt et al. 1994
). CopB is the only Cu transporter to date that has
been biochemically demonstrated to drive the accumulation of Cu(I), and
the chemically similar metal Ag(I), into reconstituted native
inside-out membrane vesicles (Solioz and Odermatt 1995
). Consistent with this biochemical function, disruption of
the CopB gene renders E. hirae cells
hypersensitive to Cu, underscoring its role in Cu extrusion during Cu
overload. The CopB protein harbors three repeats of the putative metal
binding motif MXHXXMSGMSHS in its amino terminus, a motif also found in
a periplasmic copper-binding protein of Pseudomonas
syringae (Cha and Cooksey 1991
). CopA has a single
copy of the metal binding consensus motif GMXCXXC which is found in
several metal binding proteins and is now known to be involved in Cu
ion coordination in proteins involved in Cu ion transport and
distribution (see below). Disruption of the CopA gene has no
significant effect on Cu resistance in E. hirae, however,
consistent with an important role in Cu uptake, cells with a deletion
of the CopA gene cease to grow after three days in the
presence of a Cu ion chelator, presumably due to inability to transport
Cu into the cells under conditions of Cu starvation (Odermatt et al. 1993
). These pioneering studies conducted in prokaryotic
organisms have provided valuable insight into the molecular mechanisms
by which Cu is transported in a vectorial manner, and has laid the
groundwork for identifying and understanding functional homologues in
eukaryotic cells.
In eukaryotic organisms, Cu ion transport and intracellular
distribution is understood in greatest detail in the baker's yeast,
Saccharomyces cerevisiae. This is in large part due to the
ease with which genetics can be used to isolate and study Cu ion
transport mutants, the facile molecular biology of S.
cerevisiae, and the fact that the entire genome of this yeast has
been sequenced. Figure 1
summarizes our current understanding of the yeast model for Cu uptake,
distribution and detoxification. With the exception of the
Cu-metalloregulatory transcription factors Ace1 and Mac1 (reviewed
in Koch et al. 1997
, Winge 1998
), human homologues for yeast genes that
are known to be involved in Cu ion homeostasis have been identified,
underscoring the power of yeast as a model organism for understanding
Cu metabolism and the strong conservation of Cu homeostatic mechanisms
in virtually all eukaryotes.
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). Studies
using Cu ion electrode measurements in yeast suggest that Cu ion uptake
appears to be coupled with K+ efflux with a 1:2
stoichiometry, suggesting that this process may take place via a
Cu+/2K+ antiport mechanism
(De Rome and Gadd 1987
). Although the exact mechanics of
Cu transport into yeast cells have yet to be firmly established, recent
yeast genetic studies have begun to shed light on the proteins involved
in this process. Either prior to or concomitant with high affinity
uptake, Cu(II) is thought to be reduced to Cu(I) by one or more
cell-surface Fe(III)/Cu(II) reductases encoded by the
FRE1 through FRE7 genes. (Georgatsou et al. 1997,
Hassett and Kosman 1995
) (Fig. 1)
.
Four of these FRE genes, FRE2-FRE6, are transcriptionally
regulated by Fe through the Fe-responsive transcription factor,
Aft1, while Cu transcriptionally regulates FRE1 and
FRE7 through the Cu-metaloregulatory transcription
factor, Mac1 (Martins et al. 1998
). Consistent with its
role in the reduction of Cu(II) and Fe(III) and its requirement for
high affinity uptake of these metals, the FRE1 gene is
regulated by both Mac1 and Aft1 in response to Cu and Fe, respectively.
Either subsequent to, or concomitant with reduction, Cu(I) is thought
to be delivered to the plasma membrane associated, high affinity Cu
transporters encoded by the CTR1 and CTR3 genes
(Dancis et al. 1994a
, Knight et al. 1996
). It is currently unclear whether Cu(I) ion transfer
occurs through a direct physical coupling between the FRE-encoded
metalloreductases and Ctr1/3 at the plasma membrane, followed by Cu ion
transport into the cytosol, or whether there may exist coupling
molecules which serve as intermediate Cu carriers. High affinity uptake
by Ctr1 and Ctr3 is specific for Cu and is saturable, with a
Km of 1–4 µmol/L as determined by
64Cu uptake studies in whole yeast cells
(Lin and Kosman 1990
).
Although it was initially surprising that the Ctr1 high affinity Cu ion
transporter was identified through a screen of mutants defective in Fe
transport, this observation explains the long observed, but poorly
understood link between the nutritional absorption of these two metal
ions (see below). Indeed, chromosomal disruption of the S.
cerevisiae CTR1 gene results in several phenotypes associated with
the lack of high affinity Cu uptake (Dancis et al. 1994a and 1994b
). These include poor growth in low Cu media, respiratory
deficiency (due to inability to provide Cu to cytochrome oxidase),
sensitivity to oxidative stress (due to lack of Cu incorporation into
Cu, Zn superoxide dismutase), inability to activate metallothionein
expression (due to lack of Cu to activate the Cu-metalloregulatory
transcription factor Ace1) and the absence of high affinity Fe
transport (due to inability to provide Cu to Fet3, a multicopper
ferroxidase required for high affinity iron uptake). Ctr1 is a 406
amino acid protein with three potential transmembrane domains. The
amino terminal domain, which can be modeled based on membrane
topological analysis to reside in the periplasmic space, contains
several repeats of the putative metal binding motifs M-X-M or
M-X2-M (where X is any amino acid). In addition,
the carboxyl terminal domain has cysteine, tyrosine and phenylalanine
residues, all of which are potential metal binding ligands. The
importance of these residues in Cu transport has yet to be determined.
Ctr1 is highly glycosylated and forms oligomers at the plasma membrane
(Dancis et al. 1994b
). Interestingly, levels of Cu that
exceed the Km of Ctr1 trigger the rapid and
specific degradation of Ctr1 at the plasma membrane (Ooi et al. 1996
). This represents a novel mechanism for plasma membrane
protein degradation. Studies using mutant yeast strains that have
defects in the endocytic pathway and vacuolar degradation suggest that
this process does not require internalization of Ctr1 or its delivery
to the vacuole, where proteolytic degradation often occurs. However, at
rather high Cu concentrations (10 µmol/L) it has been reported that
Ctr1 also undergoes Cu stimulated endocytosis, which may play a role in
Cu uptake or in further reducing the levels of Ctr1 at the plasma
membrane under potentially toxic Cu ion concentrations.
A second high affinity yeast Cu transporter, Ctr3, was identified as a
suppressor of the Cu starvation phenotypes associated with a
ctr1
strain (Knight et al. 1996
).
Interestingly, CTR3 gene expression in many laboratory
strains of S. cerevisiae is extinguished by the insertion of
a Ty2 retroviral-type transposable element, between the TATA box
(binding site for the transcription initiation factor, TBP) and start
site for CTR3 transcription. Although it is conceivable that
S. cerevisiae strains are at a disadvantage under some
conditions when both Cu ion transporters are functional, a more likely
explanation for its silence in some yeast strains is simply that many
domesticated S. cerevisiae strains are derived from a common
progenitor in which CTR3 was randomly silenced by a chance
transposition event (Knight et al. 1996
). This is
supported by the observation that while Ctr1 and Ctr3 can function
independently to provide high affinity Cu transport to yeast, cells
which possess both transporters have a distinct growth advantage under
Cu-limiting conditions. Ctr3 is a 241 amino acid protein that has
three putative transmembrane domains and 11 cysteine residues of which
three pairs are arranged in a potential C-C or
C-X2-C metal binding motif. What remains curious
is that, although Ctr1 and Ctr3 proteins function interchangeably in
high affinity Cu transport, there is extraordinarily little sequence
homology between these two proteins. Currently, there is no information
to support the notion that Ctr1 and Ctr3 have distinct, yet partially
overlapping roles, however, further studies are warranted to address
this question. Recent studies indicate that Cu ion uptake in S.
cerevisiae can also occur through at least three putative low
affinity systems, encoded by the FET4 (Dix et al. 1994 and 1997
), SMF1/2 (Liu et al. 1997
, Liu and Culotta 1999
) and CTR2
genes (Kampfenkel et al. 1995
). The physiological
conditions under which these putative low affinity systems operate have
not yet been defined.
It is interesting that thus far, none of the eukaryotic high affinity
Cu ion uptake proteins thought to act at the plasma membrane have the
hallmarks of ATPase domains. Although it is unclear what provides the
energy to drive Cu ions across the plasma membrane, it is possible that
the subunits that confer high affinity Cu ion transport are present in
a higher order complex that couples to an ATPase. Alternatively, the
potential role of potassium (or another ion) anti-port may serve as
the driving force, however this must be reconciled with the apparent
ATP-dependence for high affinity Cu ion transport reported
(Lin and Kosman 1990
).
Absorption of Cu in mammals.
The complexity of Cu uptake in mammalian systems is further compounded
by the need to absorb Cu from the diet and distribute it throughout the
tissues in the body. Figure 2
Aand B describe the overall scheme, as it is currently understood, for
Cu absorption and distribution in humans, both at the organ and
cellular level. What are the major questions that must be answered with
respect to Cu absorption in mammalian systems? First, how is Cu
extracted from nutrients and transported into mucosal cells that line
the intestinal wall? Secondly, how does the absorbed Cu make its way
from the intestinal mucosal cells through the baso-lateral membrane
into the blood stream? Third, what are the ligands for this Cu in the
bloodstream and how do they mobilize Cu throughout the body?
Furthermore, how is this mobilized Cu re-transported into cells
that comprise the body's organs?
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, Van Campen 1965
). Exactly how this occurs
is currently unknown. It has been proposed that Cu diffuses through the
mucous layer that covers the intestinal wall (Linder 1991
), however, given the exquisite care with which Cu is
guided into and within yeast cells, it seems unlikely that diffusion
alone would completely account for this process. Obviously, this is an
important area that remains to be resolved in our understanding of Cu
uptake in mammals, however, one candidate protein has been identified.
A human complementary DNA (cDNA) encoding a putative high affinity Cu
transport protein, denoted hCtr1, has been identified by functional
complementation of the respiratory defect in yeast cells defective in
Cu transport due to inactivation of both the CTR1 and
CTR3 genes (Zhou and Gitschier 1997
). hCtr1
is a 190 amino acid protein with significant homology to yeast Ctr1 and
Ctr3, suggesting that mammalian high affinity Cu transporters may have
evolved from both Ctr1 and Ctr3. The amino terminal domain of hCtr1 is
rich in methionine and histidine residues, reminiscent of the
methionine-rich amino terminal domain of yeast Ctr1. Furthermore,
like the S. cerevisiae Ctr1 and Ctr3 proteins, topological
analysis predicts the presence of three transmembrane domains. RNA
blotting analysis has demonstrated that hCtr1 is expressed in all
organs and tissues examined, with liver, heart and pancreas exhibiting
the highest levels of expression, intermediate levels of expression in
intestine while expression in the brain and muscle is low. Two major
mRNA transcripts of 2 and 5.5 kb were detected with approximately the
same ratios in all tissues. A less abundant 8.5 kb transcript was also
detected. The presence of these different transcripts suggests the
possible existence of forms of hCtr1 derived from alternative splicing
events, perhaps with distinct functions in Cu transport. Whether hCtr1
plays an important role in Cu uptake into intestinal mucosal cells has
yet to be firmly established.
A putative low affinity mammalian Cu transporter, hCtr2, was also
identified by sequence homology with hCtr1 and the yeast Ctr1 and Ctr2
proteins (Dancis et al. 1994a
, Kampfenkel et al. 1995
, Zhou and Gitschier 1997
). Like hCtr1,
hCtr2 mRNA is detected in all organs and tissues examined, however, in
this case the highest levels were observed in the placenta with very
low abundance observed in the liver, ovary, intestine and colon. Unlike
hCtr1, hCtr2 is unable to complement the respiratory defect in yeast
strains defective in Cu transport, thus the role of Ctr2 in Cu
homeostasis is unclear. A second putative low affinity Cu transporter,
the Nramp2 protein, has also recently been identified as a
proton-coupled metal ion transporter that transports a broad range
of metal ions (Gunshin et al. 1997
). It is interesting
that Nramp2 protein is homologous to the Smf1/Smf2 yeast metal ion
transport proteins (Liu et al. 1997
, Liu and Culotta 1999
).
Once transported into intestinal mucosal cells, how does Cu make its
way through the baso-lateral membrane? Through the combined efforts
of clinicians, molecular biologists and geneticists studying Menkes
disease, an important component in this pathway has been identified.
Menkes disease is characterized by progressive neurological impairment
and death in infancy (Danks et al. 1973
). The entrapment
of Cu in intestinal cells, kidney and vascular endothelial cells in the
blood-brain barrier in Menkes patients leads to Cu deficiency as
ascertained by defects in the activities of many Cu-dependent
proteins (Danks 1989
). The isolation of the Menkes'
disease gene (ATP7A) showed that this gene encodes a
membrane-associated P-type ATPase (Chelly et al. 1993
, Mercer et al. 1993
, Vulpe et al. 1993
). Like the E. hirae CopA protein, the Menkes
protein (MNK) contains six successive repeats of the Cu-binding
motif GMTCXXC within the amino terminal region. ATP7A mRNA is strongly
expressed in the muscle, kidney, lung, and brain, but only a trace
amount, if any, in the liver. Consistent with clinical data
demonstrating accumulation of Cu in intestinal mucosal cells in Menkes
patients, and a possible role for MNK in transport of Cu across the
baso-lateral membrane, the ATP7A gene is expressed in intestinal
epithelial cells (Murata et al. 1997
).
Since studies to date indicate that the MNK protein is involved in both
providing Cu to secreted Cu-metalloproteins, and Cu efflux from
intestinal epithelial cells, where is the MNK protein localized?
Studies in Cu-resistant Chinese hamster ovary cells, in which the
MNK genes have been amplified, showed that localization of MNK protein
is regulated by Cu ion concentrations (Petris et al. 1996
). In the presence of low Cu ion concentrations, the MNK
protein is localized in the trans-golgi network (TGN) where
it functions to deliver Cu to the secretory pathway. At elevated
concentrations, Cu stimulates the trafficking of the MNK protein from
the TGN to the plasma membrane where it is thought to be involved in Cu
efflux to protect the cells from potentially toxic levels of Cu. MNK
trafficking is energy-dependent, reversible and does not require
the synthesis of new proteins. During this process, MNK protein levels
and mRNA transcripts remain constant. The observation that Ag(I), which
is chemically similar to Cu(I), also stimulates the translocation from
the TGN to the plasma membrane suggests that it is the reduced form of
Cu [Cu(I)], that activates this process in mammalian cells.
Copper-dependent re-localization of the MNK protein requires at
least two of the six metal binding motifs in its amino terminal domain
(Strausak et al. 1999
). According to recent reports, the
third transmembrane region of MNK functions as a TGN targeting signal
(Francis et al. 1998
) and a carboxyl terminal
di-leucine is required for recycling from the plasma membrane back
to the TGN (Petris et al. 1998
). Therefore consistent
with a role in providing Cu to the secretory machinery, and in efflux
of Cu into the circulation, the MNK protein moves to appropriate
subcellular locations as a function of Cu ion concentration to carry
out these duties.
Once Cu is pumped into the circulation, what are the recipient ligands
and how do they mobilize Cu throughout the body? In the portal blood
and systemic circulation Cu is bound to albumin and histidine
(Linder 1991
). Exactly how albumin and histidine
relinquish Cu to organs and tissues is currently unclear, however, it
is possible that the bound Cu is handed off to the hCtr1 Cu
transporter, either directly or indirectly. The predominant Cu
containing protein in mammalian serum is ceruloplasmin, a glycosylated
multi-Cu ferroxidase synthesized primarily in the liver which
carries > 95% of total serum Cu (Holmberg and Laurell 1948
). Ceruloplasmin coordinates seven Cu atoms that are
incorporated during its biosynthesis and maturation in the secretory
pathway (Sato and Gitlin 1991
). Although it is not yet
established whether ceruloplasmin is involved in Cu mobilization from
the serum, the absence of ceruloplasmin in patients with
aceruloplasminemia, a genetic disorder of ceruloplasmin deficiency, has
not been shown to alter Cu levels in the peripheral tissues examined
(Miyajima et al. 1987
, Harris et al. 1998
).
Normal physiological levels of Cu in mammals is maintained through a
balance between absorption and distribution, and biliary and urinary
excretion. A central location in the body for Cu metabolism is the
liver. The importance of maintaining mechanisms for proper Cu
homeostasis in the liver is underscored by the existence of the
autosomal recessive disorder Wilson's disease (WND). Indeed, much like
the study of mutants in bacterial or yeast cells informs us about
fundamental biochemical mechanisms, the study of disease states in
humans and animal models has been very informative with respect to Cu
homeostasis. The ATP7B gene, which encodes the 160-kD WND P-type
ATPase (Bull et al. 1993
, Tanzi et al. 1993
, Yamaguchi et al. 1993
), is required for
biliary excretion of Cu and incorporation of Cu into ceruloplasmin in
the liver. Patients with Wilson's disease accumulate Cu in the liver
and brain, resulting in liver cirrhosis, neurodegeneration and the
formation of apo-ceruloplasmin. Indeed, recent gene therapy studies
have demonstrated that when the ATP7B cDNA is introduced to the
Long-Evans Cinnamon rat, a rodent model for Wilson's disease,
through adenovirus mediated gene transfer, the synthesis of
holoceruloplasmin is restored (Terada et al. 1998
).
Consistent with these observations, WND protein is localized to the
trans-Golgi network in the liver and brain where it likely
functions to incorporate Cu into ceruloplasmin (Nagano et al. 1998
) and perhaps at the canalicular site plasma membrane of
hepatocytes for excretion of Cu into the bile (Dijkstra et al. 1996
). In the presence of elevated Cu concentrations, studies
in HepG2 cells have shown that the WND protein moves from the TGN to a
cytoplasmic vesicular compartment (Hung et al. 1997
).
Although the nature of this compartment is not well defined, perhaps
the WND protein is en route to the bile canalicular membrane.
Interestingly, a 140 kD polypeptide representing a cleaved form of the
WND protein was reported to be localized to the mitochondria in
cultured hepatic cells and human tissues, rather than the TGN
(Lutsenko and Cooper 1998
). This form of WND protein is
postulated to be a product of proteolytic cleavage within the metal
binding repeats at the amino terminal domain and is targeted to the
mitochondria where it is suggested to play a role in mitochondrial Cu
ion homeostasis. How the alternative form of WND may play a role in
mitochondrial function is currently unknown. To add to the complexity,
an alternatively spliced form of WND, encoding a pineal gland
night-specific ATPase (PINA), was found to be expressed in the
pinealocytes and a subset of photoreceptors in adult rats, and
transiently in the retinal pigment epithelium and ciliary body during
retinal development (Borjigin et al. 1999
). This novel
splice variant of WND completely lacks the metal binding repeats and
the first four putative trans-membrane segments of WND.
Despite these deletions, PINA still modestly complements the defect of
Cu incorporation into Fet3 associated with yeast ccc2
strains (see below), and is proposed to function as a Cu transporter in
rat pinealocytes. Interestingly, PINA is expressed at a 100-fold higher
level at night as compared to daytime. The discovery of PINA suggests a
potential role for rhythmic Cu metabolism in pineal and/or retina
circadian function and perhaps for other body tissues. It is intriguing
that earlier studies have implicated Cu in circadian rhythms,
suggesting that serum Cu levels vary as a function of day and night.
Whether Cu regulates circadian rhythm, or circadian rhythm regulates Cu
levels have not been clearly established. Transgenic mice, which harbor
a complete deletion of PrPC, the protein
responsible for prion diseases, (see below) have only 20% of the
normal Cu content in crude membranes, synaptosomes and endosomes taken
from brain extracts (Brown et al. 1997
). These mice
exhibit alterations in their circadian rhythm and sleep patterns
(Tobler et al. 1996
).
Interestingly, the prion protein, PrPC, whose
post-translationally modified form PrpSc, is
the causative agent in Creutzfeld-Jacob disease (CJD), kuru,
Gerstmann-Straussler-Scheinker (GSS) disease and fatal familial
insomnia (FFI), collectively known as prion diseases (Prusiner 1991
), may play a role in Cu absorption in the central nervous
system. PrPC is a GPI-anchored cell-surface
glycoprotein found in the brain, spinal chord and peripheral tissues.
The normal physiological function of the prion protein is unknown, but
the observations that it binds Cu(II) (Hornshaw et al.
1995a
, Hornshaw et al. 1995b
, Prince and Gunson 1998
, Viles et al. 1999
) and that it
constantly recycles between the plasma membrane and an early endosomal
compartment (Shyng et al. 1993 and 1994
), suggests that
it may be involved Cu uptake through some as yet unidentified
mechanism. Recently, it was shown that Cu stimulates endocytosis of the
prion protein (Pauly and Harris 1998
). Like MNK protein
movement, copper stimulation of PrPc endocytosis
requires the highly conserved Cu(II)-binding repeats in the protein. It
was also shown that Cu ions facilitate the renaturation of
guanidine-denatured PrPSc molecules to form
the protease-resistant infectious prion particle (McKenzie et al. 1998
) that accumulates in the endosome due to defective
recycling of this particle to the plasma membrane. Taken together,
these observations suggest that while the normal physiological function
of the prion protein may involve Cu uptake, Cu may play a role in the
formation of the disease-causing particle by enhancing its
endocytosis. The copper-dependent relocalization of the MNK, WND
and PrPc suggests that Cu binding can stimulate
conformational changes in these proteins that are recognized by
components of the endocytic pathway resulting in their movement between
two different subcellular compartments.
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Intracellular distribution of copper |
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TOPABSTRACTINTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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, Lin et al. 1997
). Atx1 is a 73-amino acid cytosolic polypeptide that
contains a single amino terminal copy of the MTCXXC metal binding motif
that is also found in other metal binding proteins (Lin and Culotta 1995
). Extended X-ray absorption fine structure
(EXAFS) measurements indicate that Atx1 indeed binds a single Cu(I)
atom per polypeptide, as a two or three-coordinate complex with the
thiol ligands of the two conserved cysteine residues and perhaps a
third unidentified ligand (Pufahl et al. 1997
). Upon
binding Cu, the Atx1-Cu complex is proposed to make its way to the TGN
where it delivers Cu by associating with an Atx1-like amino terminal
domain in Ccc2 protein through a series of two or three-coordinate
Cu-bridged intermediates (Pufahl et al. 1997
,
Ralle et al. 1998
). The yeast Ccc2 protein is a TGN
localized ortholog of the mammalian MNK and WND P-type ATPases that
transports Cu into the secretory compartment (Yuan et al. 1995
). A number of experimental results support the model that
Atx1 delivers Cu to Ccc2 in the TGN, followed by incorporation of Cu
into Fet3, the multicopper oxidase that is an essential component of
the high affinity Fe transport complex (Lin et al. 1997
,
Pufahl et al. 1997
). Chromosomal disruption of the
ATX1 gene renders cells unable to grow in low Fe medium
presumably due to reduced high affinity Fe uptake resulting from lack
of Cu incorporation into Fet3. This defect can be corrected by addition
of Cu to the growth medium, suggesting that delivery of Cu into Fet3 is
impaired in these mutants. In vivo labeling experiments with
64Cu confirmed that indeed, incorporation of Cu
to Fet3 is defective in these mutants. The poor growth of
atx1 mutants in low iron media can also be corrected by
over-expression of CCC2, consistent with the model that
Atx1 delivers Cu ions to Ccc2 prior to incorporation into Fet3.
Furthermore, protein-protein interaction (two-hybrid) experiments
have shown that Atx1 interacts specifically in a Cu-dependent
manner with the amino terminal metal binding domain of Ccc2
(Pufahl et al. 1997
). Consistent with this interaction
and the delivery of Cu to Ccc2 by Atx1, a metal binding repeat in the
MNK protein has been demonstrated to bind Cu(I) via two cysteine
residues (Ralle et al. 1998
). Recent studies have shown
that in addition to Ccc2, efficient delivery of Cu to Fet3 requires
Gef1, a homologue of a mammalian CLC chloride channel that is found in
the trans-golgi network (Davis-Kaplan et al. 1998
, Gaxiola et al. 1998
). Gef1 is believed to
act as an anion channel to provide a counterbalancing charge that will
permit the delivery of Cu cations into a subcellular compartment that
is highly acidic.
The discovery that Cu must be supplied to an essential component of the
yeast high affinity Fe transport complex explains the old observation
of an inextricable link between Cu and Fe uptake. Early studies showed
that Cu-deficient swine developed microcytic hypochromic anemia
which can be corrected by supplementing their diet with Cu but not with
Fe (Lee et al. 1968
). Cu supplementation lowered the
abnormal Fe accumulation in these swine and increased Fe absorption
into body tissues, strongly suggesting that Cu is essential for
efficient iron uptake and mobilization in mammals. Similarly, in the
absence of functional yeast high affinity Cu uptake systems, Fet3
exists as an inactive apoprotein, and as a consequence, the Ftr1 Fe
permease protein fails to assemble properly at the plasma membrane
(Stearman et al. 1996
). As a consequence these cells are
starved for Fe. This model to explain the strict requirement for Cu in
Fe uptake and mobilization appears to be conserved in mammals at least
in terms of the fundamental proteins involved in this process. Recent
studies of mice with sex-linked anemia (sla) that accumulate Fe in
intestinal enterocytes have been shown to be defective in a gene,
Heph, encoding an integral membrane ceruloplasmin homologue
(Vulpe et al. 1999
). The Heph protein is thought to be
essential for Fe egress from the intestinal enterocyte baso-lateral
membrane into the portal circulation, providing an explanation for the
observed anemia in these animals. While Fet3 and Heph are thought to
transport Fe in opposite directions, the similarity in sequence and
Cu-dependence between these proteins is striking.
It is clear that there is a complex network of factors involved in the
distribution of Cu to distinct subcellular compartments and proteins.
Another Cu chaperone discovered in yeast, Cox17, has been shown to play
an essential role in the delivery of Cu to the mitochondria for
respiratory function (Glerum et al. 1996a
). Cox17 is a
69-amino acid polypeptide which partitions between the cytosol (40%)
and the intermembrane space of the mitochondria (60%) (Beers et al. 1997
). Cox17 contains seven potential metal binding
cysteine residues and EXAFS analysis of metallated Cox17 has
demonstrated that it binds two Cu(I) ions, within a labile binuclear
cluster, via trigonally coordinated thiolate ligands (Srinivasan et al. 1998
). Consistent with the function of Cox17 to deliver
Cu to mitochondria, inactivation of the COX17 gene results
in loss of cytochrome oxidase activity due to a failure in the assembly
of a functional multi-subunit complex leading to a corresponding
respiratory deficiency. This defect can be suppressed by the addition
of high levels of Cu to the media or by over-expression of the
SCO1 gene, or to a lesser degree the SCO2 gene,
encoding integral membrane proteins located in the inner membrane of
the mitochondria (Glerum et al. 1996b
). The generation
of yeast sco1 mutants has demonstrated that the Sco1
protein is required for the assembly of cytochrome oxidase.
Furthermore, the observation that Sco1 harbors a potential
Cu-binding domain much like that observed in cytochrome oxidase
suggests a model in which Cox17 may hand off Cu to the Sco1 receptor,
which transfers the metal ion into the cytochrome oxidase active site.
The observation that cox17 mutants are not defective in
Cu, Zn superoxide dismutase activity, and over-expression of Atx1
in cox17 mutants does not correct the corresponding
defects, suggests that Cox17 activity is largely specific for the
mitochondria.
The Atx1 and Cox17 proteins specifically deliver Cu to intracellular
compartments, the secretory pathway and mitochondria, respectively.
Insight into how cytosolic proteins acquire Cu came with the discovery
of yeast CCS (the Copper Chaperone for
SOD1), a 249-amino acid protein required for the direct
incorporation of Cu into Cu, Zn SOD (Culotta et al. 1997
). Cells that harbor a chromosomal deletion of
CCS have normal levels of Cu, Zn SOD protein but the enzyme
is inactive due to failure to incorporate Cu. These cells have no
defect in Fe uptake or cytochrome oxidase activity or the ability to
activate CUP1 expression via the Ace1 transcription factor,
suggesting that the defect is specific to SOD1 Cu loading. The
mechanism of Cu transfer from CCS to Cu, Zn SOD has not been
characterized, however, CCS appears to have two domains; an Atx1-like
domain which harbors the metal binding motif, MTCXXC, and a second
domain which is similar in sequence to a region of Cu, Zn SOD. Delivery
of Cu to Cu, Zn SOD could, in principle, occur in two steps. First, CCS
could coordinate Cu through the conserved MTCXXC motif in the Atx1-like
domain. Secondly, a protein-protein interaction between the CCS
SOD1-like domain and the Cu, Zn SOD monomer could facilitate metal
transfer from the metal-binding site in CCS to the copper binding
site in SOD. Perhaps the SOD-like domain of CCS competes with SOD
in homodimer formation sufficiently long to allow transfer of Cu into
the active site of the monomer, followed by homodimerization of the
metallated subunits to give Cu, Zn SOD.
Given the strong conservation of structure and function between yeast
and humans, it is not surprising that the intracellular distribution of
Cu ions through Cu chaperones that is observed in yeast, appears to be
conserved in mammalian cells. A human Atx1 homolog (Hah1) (Klomp et al. 1997
) has been identified; it shares structural
similarity to Atx1, and it complements the defects associated with a
yeast ATX1 gene deletion. Like Atx1, the human Hah1 (Atox1)
may function to bind Cu and supply it to the Wilson's or Menkes
disease proteins in the TGN. The other yeast Cu chaperones, CCS and
Cox17, also have human homologs. The human homolog of yeast CCS, hCCS,
directly interacts with cytoplasmic superoxide dismutase (SOD1)
(Casareno et al. 1998
). The relative cellular distribution of
hCCS in brain appears to parallel that of SOD1, consistent with a
biochemical relationship between these proteins (Rothstein et al. 1999
).
A requisite mode for metal binding by the Cu chaperones must be that
the Cu ions are coordinated to maintain a stable complex as it
approaches its target molecule or compartment, and yet the Cu must be
kinetically labile to allow metal ion exchange to take place for
transport and distribution. A number of important questions remain to
be solved with respect to Cu chaperone structure, function and
mechanism of action. The observed specificity of each chaperone for a
particular target suggests the existence of additional Cu chaperones.
For example, it is possible that a chaperone exists for targeting Cu
into the yeast nucleus for incorporation into the Cu metalloregulatory
transcription factors Ace1 and Mac1. In addition, the vacuolar
H+-ATPase encoded by VMA3, as well as
the PEP3 and PEP5 gene products required for
vacuolar assembly, are also required for appropriate Cu ion
detoxification (Eide et al. 1993
, Szczypka et al. 1997
). It has been proposed that excess Cu is stored in the
vacuole to prevent toxicity. The role of putative Cu chaperones for
targeting Cu to the vacuole and their mechanism of action is unknown.
Furthermore, the mechanism by which Cu ions are delivered from the
plasma membrane transporters to the Cu chaperones without releasing
free Cu ions into the cytosol remains unclear. It is possible that the
transporters may directly interact with the chaperones or that there
may be a central Cu ion receptor at which Cu ions are incorporated into
the chaperone. The specificity of each chaperone for its target
subcellular compartment or protein is intriguing. It is possible that
there may be a competition among the chaperones for Cu ions and that a
shift in intracellular conditions resulting from external stresses may
affect the levels of Cu chaperone expression and thereby determine the
direction of Cu ion trafficking. For example, expression of
ATX1 is partially regulated by the iron sensor, Aft1
(Lin et al. 1997
). Under conditions of iron limitation,
it is possible that increased expression of ATX1 redirects
Cu to the secretory pathway to enhance high affinity iron uptake.
Transcriptional regulation of COX17 and CCS by
metal ions has not been reported, but it is possible that under
conditions of oxidative stress, CCS protein could direct Cu ions to Cu,
Zn SOD for detoxification of superoxide anions, or that during
nonfermentative growth, delivery of Cu ions to the mitochondria for
incorporation into cytochrome oxidase may be favored to allow
respiration. In addition, it is not known if other Cu-containing
enzymes such a lysyl oxidase, dopamine ß-hydroxylase, or others, have
their own Cu chaperones or if they share common chaperones which
deliver Cu ions to the subcellular organelle where they are assembled
or active. One might expect, for example, that all secreted proteins
that utilize the classical secretory pathway may obtain their Cu
through Atx1/Hah1. While several questions remain unanswered, the
identification of the Cu chaperones has tremendously enhanced our
understanding of the mechanisms by which Cu is partitioned within the
cell.
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SUMMARY AND PERSPECTIVES |
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TOPABSTRACTINTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: CCS, copper chaperone for
SOD1; CJD, Creutzfeld-Jacob disease; Cu, copper; EXAFS, x-ray
absorption fine structures; Fe, iron; FFI, fatal familial insomnia;
GGS, Gerstmann-Straussler-Scheinken; MNK, Menkes; PINA, pineal gland
night specific ATPase; ROS, reactive oxygen species; TNG,
trans-golgi network; WND, Wilson's disease.
Manuscript received April 28, 1999. Revision accepted May 13, 1999.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONCopper uptake and absorptionIntracellular distribution of...SUMMARY AND PERSPECTIVESREFERENCES |
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D. L. Huffman and T. V. O'Halloran Energetics of Copper Trafficking between the Atx1 Metallochaperone and the Intracellular Copper Transporter, Ccc2 J. Biol. Chem., June 16, 2000; 275(25): 18611 - 18614. [Abstract] [Full Text] [PDF]
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F. W. Outten, C. E. Outten, J. Hale, and T. V. O'Halloran Transcriptional Activation of an Escherichia coli Copper Efflux Regulon by the Chromosomal MerR Homologue, CueR J. Biol. Chem., September 29, 2000; 275(40): 31024 - 31029. [Abstract] [Full Text] [PDF]
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J. Beaudoin and S. Labbe The Fission Yeast Copper-sensing Transcription Factor Cuf1 Regulates the Copper Transporter Gene Expression through an Ace1/Amt1-like Recognition Sequence J. Biol. Chem., April 27, 2001; 276(18): 15472 - 15480. [Abstract] [Full Text] [PDF]
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H. Zhou and D. J. Thiele Identification of a Novel High Affinity Copper Transport Complex in the Fission Yeast Schizosaccharomyces pombe J. Biol. Chem., June 1, 2001; 276(23): 20529 - 20535. [Abstract] [Full Text] [PDF]
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S. M. Vanderwerf, M. J. Cooper, I. V. Stetsenko, and S. Lutsenko Copper Specifically Regulates Intracellular Phosphorylation of the Wilson's Disease Protein, a Human Copper-transporting ATPase J. Biol. Chem., September 21, 2001; 276(39): 36289 - 36294. [Abstract] [Full Text] [PDF]
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I. Voskoboinik, J. Mar, D. Strausak, and J. Camakaris The Regulation of Catalytic Activity of the Menkes Copper-translocating P-type ATPase. ROLE OF HIGH AFFINITY COPPER-BINDING SITES J. Biol. Chem., July 20, 2001; 276(30): 28620 - 28627. [Abstract] [Full Text] [PDF]
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F. W. Outten, D. L. Huffman, J. A. Hale, and T. V. O'Halloran The Independent cue and cus Systems Confer Copper Tolerance during Aerobic and Anaerobic Growth in Escherichia coli J. Biol. Chem., August 10, 2001; 276(33): 30670 - 30677. [Abstract] [Full Text] [PDF]
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F. Arnesano, L. Banci, I. Bertini, F. Cantini, S. Ciofi-Baffoni, D. L. Huffman, and T. V. O'Halloran Characterization of the Binding Interface between the Copper Chaperone Atx1 and the First Cytosolic Domain of Ccc2 ATPase J. Biol. Chem., October 26, 2001; 276(44): 41365 - 41376. [Abstract] [Full Text] [PDF]
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L. A. Meyer, A. P. Durley, J. R. Prohaska, and Z. L. Harris Copper Transport and Metabolism Are Normal in Aceruloplasminemic Mice J. Biol. Chem., September 21, 2001; 276(39): 36857 - 36861. [Abstract] [Full Text] [PDF]
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E. C. Theil and R. S. Eisenstein Combinatorial mRNA Regulation: Iron Regulatory Proteins and Iso-iron-responsive Elements (Iso-IREs) J. Biol. Chem., December 22, 2000; 275(52): 40659 - 40662. [Full Text] [PDF]
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