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Environmental
Health Perspectives Supplements Volume 110, Number 5, October 2002
Molecular Mechanism of Copper Transport in Wilson Disease
Negah Fatemi and Bibudhendra Sarkar
Department of Structural Biology and Biochemistry Research, The Hospital
for Sick Children, and Department of Biochemistry, University of Toronto,
Toronto, Ontario, Canada
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Full Article in PDF
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Abstract
Wilson disease is an autosomal recessive disorder of copper metabolism.
The Wilson disease protein is a putative copper-transporting P-type ATPase,
ATP7B, whose malfunction results in the toxic accumulation of copper in
the liver and brain, causing the hepatic and/or neurological symptoms
accompanying this disease. The cytosolic N-terminal domain (~70 kDa) of
this ATPase comprises six heavy metal-associated domains, each of
which contains the conserved metal-binding motif GMTCXXC. The N-terminal
domain (Wilson disease copper-binding domain [WCBD]) has been expressed,
purified, and characterized using various techniques. The WCBD binds six
atoms of copper in the +1 oxidation state competitively, and with a greater
affinity than all other metals. The copper atom is coordinated by two
cysteines in a distorted linear geometry. Copper binds the WCBD in a cooperative
manner and induces secondary and tertiary conformation changes. Zinc binding
to the WCBD has also been characterized by circular dichroism spectroscopy
and shown to produce conformational changes that are completely different
from those induced by copper. The phosphorylation/nucleotide-binding domain
of ATP7B has also been expressed and characterized and shown to be capable
of binding ATP but lacking ATPase activity. A peptide corresponding to
the sixth transmembrane domain of ATP7B has been constructed and shown
to undergo secondary conformational changes upon binding a single atom
of copper. Finally, a chimeric protein consisting of the WCBD and truncated
ZntA, a zinc-transporting ATPase lacking the N-terminal domain, has been
constructed and analyzed for metal ion selectivity. These results suggest
that the core determines the metal ion specificity of P-type ATPases,
and the N-terminal metal-binding domain may play a regulatory role. Key
words: ATP7B/ZntA chimera, copper trafficking, copper transport, copper-ATPase,
copper binding, nucleotide-binding domain, phosphorylation domain, P-type
ATPases, Wilson disease, Wilson disease gene. Environ Health Perspect
110(suppl 5):695-698 (2002).
http://ehpnet1.niehs.nih.gov/docs/2002/suppl-5/695-698fatemi/abstract.html
This article is part of the monograph Molecular Mechanisms
of Metal Toxicity and Carcinogenicity.
Address correspondence to B. Sarkar, Research Institute,
The Hospital for Sick Children, Dept. of Structural Biology and Biochemistry,
555 University Ave., Toronto, Ontario M59 1X8 Canada. Telephone: (416)
813-5377. Fax: (416) 813-5379. E-mail: bsarkar@sickkids.on.ca
Research in this laboratory is supported by Canadian
Institute of Health Research grant MOP-1800.
Received 25 February 2002; accepted 21 May 2002.
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Wilson Disease
Wilson disease is a hereditary hepatic disease with neurological symptoms
that was first described by Kinnear Wilson in 1912 (1). This disorder
of copper metabolism is characterized by the toxic accumulation of copper in
various tissues such as the liver, kidney, brain, and placenta due to the lack
of biliary excretion of copper from the body (2). Elevated urinary copper
levels are observed, due to the accumulation of copper in the kidneys, and impaired
incorporation of copper into ceruloplasmin leads to lowered serum copper levels.
Increased liver copper concentrations are due to the deficient biliary excretion
of copper from the hepatocytes. Chelation and zinc therapy are two treatments
used for Wilson disease. Chelators such as d-penicillamine (3,4) and
trientine (5,6) are used to mobilize copper and facilitate its excretion
from the body through urine. Zinc is used to prevent copper uptake from the
intestine into portal circulation by inducing the synthesis of metallothionein
(7). Metallothionein binds copper with high affinity and is subsequently
eliminated in the feces as intestinal cells are sloughed off (8,9). Liver
transplantation may be the only hope for patients with acute liver failure,
which cannot be reversed with chelation or zinc therapy.
The Wilson Disease Gene and Its Expression
The Wilson disease gene ATP7B was localized to the q14.3 band of chromosome
13 and cloned by two independent groups in 1993 (10,11). The gene consists
of 22 exons and encodes a copper-transporting P-type ATPase (ATP7B) belonging
to and sharing many of the features of the cation-transporting P-type ATPase
family (12). The Wilson disease protein is expressed mostly in the liver
(10) and has been localized to the trans-Golgi network (TGN) by
immunohistochemical studies (13,14). Such studies have also shown the
trafficking of the ATPase from the TGN to cytoplasmic vesicles in response to
an increase in copper concentration (13,15); this copper-dependent cycling
of ATP7B probably accounts for the biliary excretion of copper from the liver
and correlates well with the Wilson disease phenotype.
The Wilson Disease Copper-Transporting P-Type ATPase
Sequence analysis has identified the Wilson disease ATPase as a copper-transporting
P-type ATPase (Figure 1).
More specifically, the Wilson disease ATPase has several features distinguishing
it from other members of the P-type ATPase family, classifying it as a CPx-type,
type I, or heavy-metal P-type ATPase. Other members of the CPx-type ATPases
are the bacterial copper (CopA) (16) and zinc (ZntA) (17) ATPases,
and in humans, the Menkes disease copper-transporting ATPase (ATP7A) (18-20).
The major difference between the CPx-type ATPases and other P-type ATPases is
the presence of an additional pair of transmembrane helices and a cytoplasmic
metal-binding domain at the N terminus. In addition to a pair of cysteines flanking
the conserved proline residue in the transduction domain, the histidine and
proline residues of the SEHPL sequence motif are highly conserved in heavy metal-transporting
ATPases. The mutation of the conserved histidine residue of this motif, H1069Q,
is one of the most common mutations found in Wilson disease (21,22).
The involvement and the role of the SEHPL motif in the copper transport scenario
are still not clear, although its importance is reflected in its conservation
and its correspondence to a disease-causing mutation. Site-directed mutagenesis
of the conserved histidine reveals that the motif is somehow involved in metal-ion-stimulated
ATPase activity and phosphorylation of the transporter (23,24).
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Figure 1. The Wilson disease
protein is a copper-transporting CPx-type ATPase. The transporter consists
of transmembrane, phosphorylation, nucleotide-binding, and actuator domains
common to other P-type ATPases. Features unique to CPx-type ATPases include
a large cytoplasmic metal-binding domain containing between one and six
metal-binding motifs, a pair of N-terminal transmembrane helices, CPC,
and the SEHPL motifs.
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In addition to its ATP-driven copper transport role at the TGN where copper
is incorporated into ceruloplasmin (25,26), the Wilson disease protein
is also thought to be involved in the excretion of copper into bile at the canalicular
membrane (27). The copper-stimulated trafficking of the transporter between
the TGN and the canalicular membrane may involve the N terminus and is not clearly
understood (28). It has been shown that the presence of at least one
copper-binding domain close to the membrane channel is necessary for copper-induced
redistribution of both the Wilson (29) and the Menkes disease transporter
(30). Copper-induced conformational changes observed in the N-terminal
copper-binding domain of the Wilson disease ATPase (WCBD) have been suggested
as a mechanism behind this cellular trafficking. Protein-protein interactions
or changes in the global conformation of the transporter may render a recognition
site accessible to the components of the membrane-protein-sorting machinery
and signal the protein to traffic between the TGN and the plasma membrane in
a copper-dependent manner. Site-directed mutagenesis of residues in transmembrane
helices 4 and 6 has implicated their involvement in the copper-dependent trafficking
of the transporter. Tyrosine and dileucine motifs (31,32) in the Menkes
disease transporter C terminus have also been suggested as recognition and trans-Golgi
retention signals recognized by the vesicular trafficking machinery.
Characterization of Copper Binding to the WCBD
The WCBD has been the subject of intense study in our laboratory. This 70
kDa N-terminal domain encompassing all six metal-binding motifs has been expressed,
purified, and shown to bind six atoms of copper in the +1 oxidation state. Using
immobilized metal affinity chromatography, we have shown that the WCBD is able
to bind different transition metals with varying affinities: Cu(II) > >
Zn(II) > Ni(II) > Co(II) (33).
We employed competition 65Zn blotting analysis to investigate the
ability of the WCBD to bind copper and other transition metals (33).
Of the transition metals tested, Cd(II), Au(III), and Hg(II) were able to successfully
compete with zinc for binding to the domain. Copper was the strongest competitor
and displayed a distinct cooperative binding mechanism not observed with the
other transition metals.
Our X-ray absorption spectroscopy (XAS) studies of the WCBD containing substoichiometric
amounts of copper have provided a wealth of detailed structural information
regarding this domain (34). The X-ray absorption near edge structure
spectra display a characteristic feature of the 1s to 4p transition of Cu(I)
at 8,983 eV, verifying that copper bound to the WCBD is in the +1 state. The
intensity of the transition at 8,983 eV, which is indicative of the geometry
around the copper atom, is weaker than that of linear copper thiolate complexes
but stronger than that of trigonal compounds. Extended X-ray absorption fine
structure data show that the first coordination sphere consists of two sulfur
atoms with a Cu-S distance of 2.17-2.19 Å. This is similar to
the Cu-S bond distance observed in Menkes disease protein and falls between
the distances observed for trigonal and linear Cu(I)-thiolate complexes
(35). These observations suggest that the copper atom is coordinated
by two cysteines in a distorted linear geometry.
Circular dichroism (CD) spectroscopy results show that copper binding induces
conformational changes in the WCBD (34). The secondary structure region
(200-270 nm) shows an increase in ellipticity upon binding of increasing
amounts of copper, suggesting a stabilization of secondary structures relative
to the apo state. The changes observed in the aromatic region (250-350
nm) were in agreement with those in the secondary structure region. The greatest
changes in the spectra occur between the 2:1 and 4:1 copper-bound forms. The
2:1 and 4:1 copper-bound forms have very similar secondary structure but significantly
different tertiary structure, which may reflect the cooperative nature of copper
binding.
Characterization of Zinc Binding to the WCBD
Studies in this laboratory have also characterized the binding of zinc to
the WCBD (36). The WCBD is able to bind six molar equivalents of zinc
and undergo conformational changes that are completely different from those
induced by copper binding. Our CD spectral analyses show that zinc binding is
accompanied by an overall loss of secondary structure. This is further supported
by our XAS data that indicate that the zinc-binding sites are occupied mostly
by nitrogen and not sulfur atoms. Therefore, although the WCBD has the ability
to bind several different metals, the different conformations induced by different
metals may allow the transporter to differentiate between copper and other metals
in vivo. To delineate the metal ion selectivity and to investigate whether
this domain contributes to metal ion recognition by the transporter, a collaborative
effort was undertaken to construct an ATP7B/ZntA chimeric protein (37).
Characterization of Metal Ion Selectivity of the Chimeric
ATPase
ZntA is a CPx-type ATPase from Escherichia coli, which confers resistance
to Pb(II), Cd(II), and Zn(II) (38). This protein has a single copy of
the metal-binding motif, whereas ATP7B has six copies. Two chimeric proteins
have been constructed in which the N-terminal of ZntA is replaced with either
the entire N-terminal domain of ATP7B or just the sixth metal-binding motif
of ATP7B (37). Both chimeras confer resistance to and display activity
with Pb(II), Cd(II), and Zn(II), all of which are substrates of ZntA. There
is no resistance or activity toward copper and silver, which are the substrates
of ATP7B. Although the N-terminal domain of ZntA is not essential for its activity
or selectivity toward a particular metal, it is required for full catalytic
activity and cannot be replaced by the N-terminal domain of ATP7B. The results
of this study suggest that the core of the P-type ATPase determines metal ion
specificity and that the N-terminal plays a regulatory role, perhaps by interacting
in a metal-ion-specific manner with the other parts of the transporter.
Copper binding to the WCBD appears to elicit the conformational changes required
to regulate the activity of ATP7B.
Core Elements within the Transduction Channel May Determine
Substrate Specificity
Ca-ATPase (39), Na,K-ATPase (40), and H-ATPase (41) are
three P-type ATPases for which a great deal of structural information is available.
In these P-type ATPases, transmembrane domains M4, M5, and M6 form part of the
channel and contain residues critical to cation binding. In ATP7B, transmembrane
domains TM6 and TM7 are predicted to correspond to M4 and M5 of P-type ATPases
and form part of the channel (42). In a clever experiment that highlighted
the central role of M4, Na,K-ATPase's cation-binding specificity was altered
to that of H,K-ATPase by mutating residues within the channel (43). TM6
of ATP7B corresponds to M4 of Ca-ATPase, and both transmembrane domains contain
a conserved proline residue found in all P-type ATPases. In the heavy metal
ATPases, highly conserved cysteine residues flank this proline residue to form
a CPC motif. Mammalian copper-transporting ATPases have an additional conserved
cysteine, forming a CXXCPC motif. Site-directed mutagenesis studies of the cysteine
residues in the CPC motif have revealed it to be essential for the copper transport
function of the ATPase (24,44). The CPC motif is predicted to be one
of the copper-binding sites in the channel.
Identification of Core Residues Involved in Metal Ion Binding
and Specificity
To further characterize copper binding to the CPC motif, we constructed a
peptide corresponding to residues from TM6 of ATP7B . Single C/S mutants of
this peptide have also been synthesized. Preliminary CD results show that the
peptide binds a single atom of copper and that copper binding induces secondary
conformational changes in the peptide (45). Further studies in this area
are aimed at the identification of other residues within the transduction channel
that confer copper selectivity to ATP7B.
Characterization of the Phosphorylation/Nucleotide-Binding
Domain
The second largest cytosolic domain of ATP7B, which encompasses the phosphorylation
(P) subdomain, nucleotide-binding (N) subdomain, and the hinge region, has been
expressed and purified in our laboratory and by others. In our laboratory, it
has the ability to bind the fluorescent ATP analog TNP-ATP, but it has no ATPase
activity (46). We speculate that this is may be due to the absence of
other domains required for ATPase activity, in particular the actuator (A) domain.
Mutational as well as structural analyses of other P-type ATPases suggest the
involvement of the A domain in energy transduction and hydrolysis of the phosphoenzyme
intermediate, formed during the catalytic cycle (39).
Gapped BLAST (basic local alignment search tool) alignment of Cu-ATPase and
Ca-ATPase (42), together with the presence of highly conserved residues,
suggests that the general mechanism and cation transport proposed for P-type
ATPases likely apply to CPx-type heavy metal-transporting ATPases as well
(39,47).
The sequence alignment of P-type and CPx-type ATPases reveals that ATP7B has
large deletions in its A domain and also in its N domain. The P domain, however,
is highly conserved. These observations give rise to a number of questions regarding
how these differences in corresponding domains affect the mechanism of copper
transport by ATP7B compared with the general mechanism proposed for P-type ATPases.
Proposed Mechanism for Copper Transport by the Wilson Cu-ATPase
Atox1, implicated as the metallochaperone for ATP7B, probably delivers copper
ions to the WCBD (48-50). Atox1 itself has a copper-binding motif
and is thought to specifically interact through complementary electrostatic
surfaces with the copper-binding motifs and exchange copper (3). However,
this may not be the only way by which the WCBD obtains its copper. Not all the
copper-binding motifs found in the WCBD possess the complementary electrostatic
patches necessary for interaction with Atox1 (51), and the list of other
possible copper-binding proteins is growing. Preliminary metalloproteomic studies
in our laboratory have identified a number of proteins, previously not classified
as possessing any copper-binding activity. Many of these proteins themselves
contain the CXXC motif or are associated in complexes with proteins that contain
the CXXC motif (52). Interestingly, some of these proteins are also involved
in the protein folding and disulfide bond isomerization pathways. Further investigation
is required before any of these other candidates can be ruled out for delivery
of copper to ATP7B.
On the basis of the degree of similarity between ATP7B and other P-type ATPases
and structural/functional studies of this transporter, we can begin to form
a model for the mechanism of copper transport by ATP7B based on the model proposed
for classical P-type ATPases (39,53). The WCBD probably serves as the
initial site for metal ion binding to the transporter. Specific interaction
between the WCBD and its nucleotide binding/phosphorylation domain has been
demonstrated, and binding of copper to the WCBD has been shown to dissociate
this interaction (54). Although the WCBD has the ability to bind different
metals, zinc binding studies seem to suggest that only the binding of copper
induces the correct conformational changes necessary for the WCBD to dissociate
from the other domain. This conformational change is tied to cytoplasmic copper
concentrations, so it is possible for the copper-bound state of the WCBD to
regulate the activity of the transporter. Copper binding to the WCBD may be
what drives the transporter from an inactive or low activity state, where the
cytoplasmic domains are all bound by low-copper WCBD, to an active state where
the high-copper WCBD has released the other cytoplasmic domains.
Although the cytoplasmic domains of ATP7B and Ca-ATPase are very similar,
there are large deletions and sequence alterations observed in the actuator
domain and nucleotide-binding domains of ATP7B, which may allow for the specific
interaction of the WCBD with these domains. After the dissociation of the domains,
the mechanism of copper transport most likely progresses through the same E1-E2
intermediates that are proposed for other P-type ATPases (39).
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Last Updated: October 4, 2002
