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of the photosynthates is transferred that are essential for the activity of a

from Ostreobium to the coral, Primer number of important cellular enzymes.
extending the time it can survive Additionally, the Irving–Williams series
without zooxanthellae. describes the relative stabilities of
Copper: An essential metal ion complexes and predicts
So, what’s the verdict, good or bad?
Boring algae clearly have important
metal in biology that Cu can displace other metals,
such as zinc, from their cognate
functions in reef ecosystems and will ligands in metalloproteins, resulting
influence how they cope with climate Richard A. Festa and Dennis J. Thiele* in inappropriate protein structures or
change and ocean acidification in inhibition of enzymatic activity. Here we
the near future. However, we cannot Life on Earth has evolved within provide a brief overview of some roles
yet give a verdict as to whether they a complex mixture of organic and for Cu in biology in bacterial, fungal,
will act as a buffer against these inorganic compounds. While organic plant and mammalian systems, and
environmental changes or make the molecules such as amino acids, we outline key ways in which Nature
situation worse. Little is known about carbohydrates and nucleotides balances the acquisition, distribution
the ecophysiological diversity of form the backbone of proteins and and regulation of Cu. It will become
boring algae, hence their response is genetic material, these fundamental clear that, as life evolved, more
difficult to predict. Recent research components of macromolecules complex roles for Cu arose, concurrent
shows that the genotypic diversity are enzymatically synthesized and with the elaboration of mechanisms
of Ostreobium is remarkably rich, ultimately degraded. Inorganic to tightly regulate acquisition and
leading us to speculate that this will be elements, such as copper (Cu), iron distribution of Cu and provide
reflected in their physiological diversity and zinc, once solubilized from the protection against Cu toxicity.
and geographical distributions. While Earth’s crust, are neither created
this will complicate the interpretation nor destroyed and therefore their Copper in prokaryotes
of research outcomes not taking this homeostatic regulation is under In general, prokaryotic organisms
diversity into account, it also opens up strict control. In the fascinating field have adopted a limited role for Cu in
an exciting avenue of research into the of ‘metals in biology’, by virtue of their biochemistry and physiology.
details of the functional multiplicity of direct interactions with amino acid Almost all anaerobic bacteria and
boring algae. side-chains within polypeptide chains, all anaerobic Archaea are limited Cu
metals play unique and critical roles users, likely reflective of the limited
Where can I find out more? in biology, promoting structures and availability of the metal under these
Fine, M., and Loya, Y. (2002). Endolithic algae: an conditions, and may be representative
alternative source of photoassimilates during
chemistries that would not otherwise
coral bleaching. Proc. Roy. Soc. B Biol. Sci. be available to proteins alone. of the majority of life in primordial,
269, 1205–1210. After the rise of photosynthetic anaerobic Earth. Yet, while Cu is not
Garcia-Pichel, F., Ramirez-Reinat, E., and
Gao, Q.J. (2010). Microbial excavation of organisms such as the cyanobacteria, widely used by these prokaryotes,
solid carbonates powered by P-type oxygen accumulated in the many of their genomes encode Cu
ATPase-mediated transcellular Ca2+ transport. exporters and Cu delivery proteins,
Proc. Natl. Acad. Sci. USA 107, 21749–21754.
atmosphere and oxygenated the
Gutner-Hoch, E., and Fine, M. (2011). Genotypic oceans. This led to a decrease in the known as chaperones, to protect
diversity and distribution of Ostreobium solubility of iron and an expansion of against the toxic effects of Cu. The
quekettii within scleractinian corals. Coral
Reefs 30, 643–650. the biological role of Cu, suggesting majority of the prokaryotes that use
Koehne, B., Elli, G., Jennings, R.C., Wilhelm, there was a shift from the exclusive Cu express cytochrome c oxidase, the
C., and Trissl, H.W. (1999). Spectroscopic last enzyme in the respiratory electron
and molecular characterization of a long
use of iron in biology to embrace
wavelength absorbing antenna of Ostreobium similar, though not identical, roles for transport chain. Typical Cu-containing
sp. Biochim. Biophys. Act. 1412, 94–107. Cu. One property of Cu that drives its enzymes such as cytochrome c
Odum, H.T., and Odum, E.P. (1955). Trophic
structure and productivity of a windward diverse roles in structure and catalysis oxidase, NADH dehydrogenase 2, and
coral reef community on Eniwetok atoll. Ecol. is its existence in either a reduced tyrosinases reside in the cytoplasmic
Monogr. 25, 291–320. membrane or periplasm where they
Tribollet, A. (2008). The boring microflora in
(Cu+) state or an oxidized (Cu2+) state.
modern coral reef ecosystems: a review of its Since Cu+ has an affinity for thiol and are loaded with Cu, thereby reducing
roles. In Current Developments in Bioerosion, thioether groups (examples found risk to cytoplasmic components.
M. Wisshak and L. Tapanila, eds. (Berlin:
Springer), pp. 67–94. in cysteine or methionine), and Cu2+ It is currently unclear how Cu is
Tribollet, A., Godinot, C., Atkinson, M., and exhibits a preferred coordination to imported into bacterial cells. Current
Langdon, C. (2009). Effects of elevated pCO2 hypotheses include the presence of
on dissolution of coral carbonates by microbial
oxygen or imidazole nitrogen groups
euendoliths. Global Biogeochem. Cycles 23, (found in aspartic and glutamic acid, a broad-spectrum cation transporter
GB3008. or histidine, respectively), these metal and, in the case of the heavily
Verbruggen, H., Ashworth, M., LoDuca, S.T.,
Vlaeminck, C., Cocquyt, E., Sauvage, T., ions can participate in a wide spectrum Cu-dependent methanotrophs which
Zechman, F.W., Littler, D.S., Littler, M.M., of interactions with proteins to drive use Cu as a catalytic co-factor in
Leliaert, F., et al. (2009). A multi-locus methane mono-oxygenase, the use of
time-calibrated phylogeny of the siphonous
diverse structures and biochemical
green algae. Mol. Phylogenet. Evol. 50, 642–653. reactions (Table 1). Moreover, in the the Cu-binding peptide methanobactin.
process of moving between Cu+ and A general model for Cu homeostasis
1Phycology Research Group, Ghent Cu2+ states, free intracellular Cu can in bacterial cells can be considered
University, Krijgslaan 281/S8, 9000 Gent,
generate hydroxyl radicals, which with respect to three basic functions
Belgium. 2Institut de Recherche pour le
Développement, UMR LOCEAN-IPSL, can damage proteins, nucleic acids, that are focused on protection from
France. and lipids, and can interfere with Cu more than Cu utilization: sensing,
E-mail: [email protected] the synthesis of iron–sulfur clusters intracellular mobilization, and export
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Table 1. Examples of Cu-dependent proteins and Cu homeostasis proteins.

Protein Function Bacteria Fungi Animals Plants

Transcriptional regulators
Ace1 Transcriptional activation in high Cu conditions X
CopY Bacterial Cu metalloregulatory repressor X
CsoR Bacterial Cu metalloregulatory repressor X
Mac1 Transcriptional activator in low Cu conditions X
CueR Bacterial Cu metalloregulatory repressor X
Mtf1 Metalloregulatory transcription factor X
Spl7 Transcriptional activator responding to Cu deficiency X
Chaperones/storage
Atox1 Metallochaperone delivering Cu to P-type ATPases X X X
Ccs Delivers Cu to the Cu/Zn SOD1 X X X
CopZ Bacterial Cu chaperone X
Metallothionein Low molecular weight, cysteine-rich metal-binding and X X X X
detoxification
Cell surface/secretory compartment transporters and receptors
P1B-type ATPases Cu+-exporting proteins X X X X
Ctr Cu+-importing proteins X X X
Ethylene receptor Uses Cu as a cofactor for ethylene signaling X
Oxidoreductases
Ascorbate oxidase Reduction of L-ascorbate X
Dopamine-monooxygenase Tyrosine metabolism X
Galactose oxidase Reduction of galactose X
Amine oxidase Oxidation of diamines X X X X
Electron transfer/energy production/blue Cu proteins
Cytochrome c oxidase Necessary for the last step of respiration X X X X
Plastocyanin Electron transfer during photosynthesis X X
NADH dehydrogenase Electron transfer from NADH to coenzyme Q X X X X
Nitrite reductase Reduces nitrite to nitric oxide X
Amicyanin Electron-accepting intermediate in the conversion of X
methylamine to formaldehyde and ammonia
Free radical scavenging
Cu/Zn SOD Free radical scavenging X X X X
Oxidase
Laccase Melanine production X X X X
Lysyl oxidase Catalyzes the formation of collagen and elastin precur- X
sors, extracellular
Ceruloplasmin MultiCu oxidase X
Hephaestin Transmembrane ferroxidase, transports iron from the X
intestine to the circulatory system
Multicopper ferroxidase Cu-dependent iron uptake X X X
Monooxygenase
Methane monooxygenase Oxidizes C–H bond in methane X
Phenylalanine hydrolase Hydroxylation of the aromatic side chain of phenyl­ X
alanine to generate tyrosine
Tyrosinase Monophenol monooxygenase, catalyzes the oxidation X X X X
of phenols, melanin synthesis

(Figure 1). Many bacteria are primed some Gram-negative species contains array of metalloproteins located within
to sense and respond to elevated additional Cu detoxification and export organelles such as mitochondria,
Cu levels by one of three families of mechanisms, such as Cu+ oxidases, chloroplasts, and the secretory
metalloregulatory repressors (CopY, Cu chaperones, and non-specific outer compartments. Furthermore, with the
CsoR, and CueR) that, under low membrane metal cation transporters. subsequent appearance of multicellular
Cu conditions, repress transcription Once Cu is exported from the organisms came the requirement to
of genes encoding the Cu export cytosol, Cu-responsive transcriptional regulate Cu allocations to specific
machinery. Cu is exported from repressors rheostatically dampen tissues according to varying metabolic
bacterial cells by polytopic integral transcription of the genes encoding needs. Thus, Cu homeostasis became
membrane Cu+ transporters, P1B-type the Cu-transporting ATPases. Archaea a more complex and tightly controlled
ATPases, which are characterized by appear only to encode Cu exporters process at both an intracellular and
Cys–X2–Cys motifs (where X is any and not any of the known Cu importers intercellular level.
amino acid) or His-rich domains in their or chaperones identified in bacterial
amino termini and conserved His–Pro cells or in eukaryotes. Fungi
and Cys–Pro–Cys/His motifs within As the model single-cell eukaryote,
specific transmembrane domains. Copper in eukaryotes much of the basic nuts and bolts
Through such ATPases, Cu is exported With the evolution of single-cell that mediate Cu homeostasis were
out of the cytoplasm into the periplasm eukaryotes came the new challenge first described in Saccharomyces
or out of the cell. The periplasm of of deliverying Cu to an expanding cerevisiae, and the enhanced
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complexity of Cu balance in yeast, Cu metalloproteins. Atx1 is structurally Methanobactin Non-specific metal

cation transporter?
compared with that found in similar to the cytoplasmic Cu-binding
prokaryotes, can easily be appreciated domains of Ccc2, providing similar
(Figure 2). In S. cerevisiae Cu is taken protein surfaces to mediate Cu transfer
up by two apparently functionally between the two proteins. The Cu, Zn
redundant high-affinity Cu transporters, superoxide dismutase (Sod1), which
Ctr1 and Ctr3, or a low-affinity disproportionates the potentially toxic Cytochrome P-type
transporter, Fet4, after Cu2+ is reduced superoxide anion, localizes both to the c oxidase ATPase
at the plasma membrane to Cu+ by cytoplasm and to the mitochondrial
cell-surface metalloreductases, such intermembrane space. Ccs1, the Cu
as Fre1. The Ctr family of importers chaperone for Sod1, has a domain Chaperone

have characteristic methionine-rich that structurally resembles Sod1. Ccs1

amino termini that are thought to bind directly interacts with Sod1 in the
extracellular Cu+, potentially enhancing cytoplasm and intermembrane space,
Repressor
the local concentration of the metal. delivering Cu to Sod1 in a complex
Additionally, there is a Met–X3–Met series of reactions. While mitochondrial
motif within the second of its three cytochrome oxidase has a critical Current Biology
transmembrane domains, with the requirement for Cu, the mitochondrial
methionines likely functioning in Cu+ matrix harbors a significant pool of Figure 1. Copper homeostasis in bacteria.
binding during translocation across Cu that has been calculated to be far The themes of Cu homeostasis are conserved
the membrane, perhaps to carefully in excess of the needs of cytochrome among Kingdoms. In this and the following
control the Cu+ ion as it traverses the oxidase, suggesting that mitochondria figures, import factors are shown in orange,
lipid bilayer to prevent damage and to may harbor a storage pool of Cu. chaperones in blue, export factors in yellow, and
provide vectorial movement. Mac1 is However, the molecular mechanisms transcriptional regulators in gray. The general
bacterial Cu response activates an operon
a nuclear Cu-sensing transcriptional by which Cu is imported into and consisting of a transcriptional repressor, a
regulator that is responsible for mobilized from mitochondria chaperone and a P-type exporter. In the absence
activating the CTR1, CTR3 and FRE1 are not yet clear. Several of Cu, transcriptional repressors such as CueR,
genes under low Cu conditions. mitochondrial-associated proteins, CsoR and CopY maintain repression of the Cu
Endocytosis and degradation of the including Cox17, Sco1 and Sco2, response machinery. In the presence of Cu,
Ctr1 protein is promoted under high which are conserved from yeast to repressor proteins bind Cu and dissociate from
their DNA binding sites in promoter regions,
Cu conditions. If external sources of humans, are involved in the delivery resulting in derepression of genes encoding
Cu are vanishingly low, S. cerevisiae of Cu to cytochrome oxidase, and chaperones and P-type ATPases that facilitate
responds by mobilizing Cu stores mutations in human Sco genes are protection against Cu toxicity by sequestration
from the vacuole, a process carried associated with severe infantile and export. Cytochrome c oxidase, located in
out by Ctr2, and a vacuolar-localized cardiomyopathy, underscoring the the bacterial membrane, is the most common
metalloreductase, Fre6. Branching out importance of deciphering how cuproenzyme in bacteria. The mechanism of
Cu import in bacterial cells is currently poorly
to other yeast, Schizosaccharomyces cytosolic Cu is routed to and from defined but may include a relatively non-metal-
pombe encodes a major facilitator mitochondria. specific cation transporter (green). Alternatively,
superfamily-type transporter, called Although Cu uptake and distribution methanotrophic bacteria may use a non-
Mfc1, that is responsible for Cu mechanisms in yeast are able to cope translationally synthesized Cu-binding peptide,
acquisition during meiosis, opening up with a broad range of Cu availability, methanobactin, to acquire Cu.
the possibility for cell-cycle-specific the expression of genes encoding
and cell-type-specific Cu transporters the Cu detoxification proteins called factor, Ace1, under conditions of high
and Cu-dependent processes in other metallothioneins is dialed up as cells Cu. Therefore, S. cerevisiae activates
organisms. encounter increases in environmental distinct genes in response to low and
Given that eukaryotic cells have Cu. The S. cerevisiae Cup1 and Crs5 high Cu using distinct Cu-sensing
elaborate compartments and organelles metallothioneins scavenge excess Cu transcription factors.
in which Cu-dependent proteins reside by tight coordination with cysteine
or traverse on their journey to be thiolates, buried from solvent, so that Mammals
secreted, tightly controlled intracellular it is poorly exchangeable and therefore Much of the cellular Cu acquisition
Cu-delivery mechanisms have evolved. not highly reactive. Metallothioneins and trafficking machinery in
Genetic studies in yeast identified two from different species rarely share mammals is similar to that found in
such small Cu-chaperone proteins, sequence similarity and are usually yeast (Figure 3). As yeast cells use
Atx1 and Ccs, which directly bind identified based solely on their high Ctr family members to transport
Cu near the surface of their number of cysteines. In fact, while extracellular Cu+ across the plasma
three-dimensional structure so metallothioneins were originally membrane, several studies indicate
that it is protected, yet exchangeable thought to be restricted to eukaryotes, that Ctr1 is the primary transporter
for other biological ligands. Atx1 their presence in Mycobacterium responsible for dietary Cu uptake into
interacts directly with the Ccc2 protein, tuberculosis and Synechococcus the intestinal epithelium. Unlike the
a P-type Cu-transporting ATPase species suggests they are also transcriptional activation of yeast Ctr1
similar to that found in bacterial cells, widely distributed in prokaryotes. The and Ctr3 in response to Cu deficiency,
which pumps Cu into the lumen of CUP1, CRS5 and SOD1 genes are mammalian Ctr1 is regulated at
the secretory compartment where it is transcriptionally activated by a second the level of elevated Cu-induced
incorporated onto ligands of secreted Cu metalloregulatory transcription endocytosis and degradation as a
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Cu+ in intestinal enterocytes is shuttled

to the ATP7A Cu-transporting P-type
ATPase at the basolateral membrane
Cu2+ Cell wall by the Atox1 Cu chaperone and
pumped into the portal circulation,
where it makes its way to the liver,
the major Cu storage organ. ATP7A
Cu+ Cup1 plays crucial roles in moving Cu across
Fre1 other polarized cell layers, including
Crs5 the placenta and the blood–brain
barrier, to ensure adequate Cu in the
developing fetus, and to meet the
Ccs high demands for brain development
and function. Similar to Ccc2 in yeast,
ATP7A is also important for the delivery
of copper to nascent proteins in the
Atx1
Golgi apparatus. In mammals, ATP7A
is expressed in many tissues except
the liver, where its expression is high in
Sod1 neonatal mice and diminishes during
Cox17 maturation. In the liver and other
tissues, a homologous Cu-transporting
ATPase, ATP7B, is important for
Golgi loading Cu on ceruloplasmin, a
secreted Cu-containing ferroxidase
in the plasma that has a key function
Sco1 Sco2 in peripheral iron distribution. ATP7B
Cox also mobilizes excess Cu into the bile,
preventing tissue Cu overload. Recent
work suggests that mice lacking Ctr1
Mitochondria
specifically in the cardiomyocytes
Mac1 of the heart develop a myopathy
CTR1/CTR3/FRE1
secondary to Cu deficiency and, in the
process, release an unknown signal
Ace1 into the bloodstream that stimulates
CUP1/CRS5/SOD1
the activation of hepatic and
intestinal ATP7A expression and
the mobilization of Cu into the
Nucleus
bloodstream. How mammals sense
Current Biology tissue Cu deficiencies and elaborate
signals that communicate with Cu
Figure 2. Copper homeostasis in yeast. acquisition and storage organs will
Unicellular organisms such as yeast have increased complexity for the distribution of Cu to be an important area for further
intracellular proteins and compartments. Most notably, chaperones are utilized to safeguard investigation.
the cell from free Cu and to expedite delivery, as the metal is delivered to intracellular Cu-con-
taining proteins. Ccs delivers Cu after reduction from Cu2+ to Cu+ by the Fre1 metalloreductase, Plants
and import by the Ctr1 and Ctr3 Cu transporters, to Sod1 to protect against oxidative stress.
The Cu homeostasis machinery in
Atx1 is a chaperone that delivers Cu to Ccc2 where Cu is translocated into the Golgi apparatus
to be loaded onto cuproenzymes. Cup1 and Crs5 are metallothioneins that protect yeast cells plants has undergone a dramatic
from Cu toxicity. Mac1 and Ace1 are transcriptional activators that respond to Cu starvation expansion in complexity over the
and excess, respectively. The precise mechanisms whereby cytosolic Cu is delivered to mito- other forms of life explored to date,
chondria for loading onto cytochrome c oxidase (Cox) by Cox17, Sco1/2 and other proteins perhaps due to the presence of
are currently unknown. both mitochondria and chloroplasts,
their relatively sessile lifestyle, and a
means to rheostatically regulate the indirect manner, via the MTF-1 collection of Cu-dependent proteins
steady-state levels of Ctr1 and the transcription factor. that are unique to plants (Figure 4).
abundance of Ctr1 at the plasma Metazoans not only need to acquire For example, Arabidopsis thaliana
membrane. Mammals also express Cu and mediate its intracellular has six Ctr-family transporters,
the Atox1 (homolog of Atx1) and Ccs distribution, they must also parse Cu COPT1–COPT6, each with a distinct
Cu chaperones that are functionally out to peripheral tissues where it drives tissue-specific expression and
analogous to those in yeast. Cu-specific cellular processes, such as the high subcellular localization pattern.
transcriptional control has not been demand for mitochondrial oxidative COPT1, the most extensively studied
characterized in mammalian cells, phosphorylation in brain and heart transporter, is thought to be largely
although Cu activates metallothionein tissue. In mammals, Cu transported responsible for root Cu acquisition, but
gene transcription, in an apparently across the apical membrane by Ctr1 COPT2 also localizes to the plasma
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membrane in root tissues. Similar to

Ctr2 in mammals, COPT4 does not
appear to play a prominent role in
Cu import. COPT5 may play a role in
mobilization of vacuolar Cu stores, and
COPT3 and COPT6 have less well- Sod1
defined functions.
The P-type ATPases, known as
heavy metal P-type ATPases (HMAs) in
plants, are composed of at least eight ATP7A
identified members in Arabidopsis. Ccs
HMA1 to HMA4 are divalent cation
transporters implicated in the export
of not only Cu2+, but also Zn2+ and Atox1 ATP7B
Ctr1
Cd2+. In contrast, HMA5 to HMA8 are
thought to serve as monovalent Cu+
ion transporters. HMA7 (also known as
RAN1) is, to a large extent, responsible

AT 7B
for the biogenesis of ethylene receptors

AT
P7
(ETRs; ethylene is a key hormone for

P
A
plant signaling), by delivering Cu to
ETR1 en route through the endoplasmic
Golgi
reticulum, and it is not unreasonable
that other secreted cuproproteins might Cox
also receive Cu in this manner. HMA5,
primarily expressed in roots, is likely Mitochondria MTF1 MTI/II
responsible for root Cu detoxification.
HMA6 (also known as PAA1) and HMA8
Nucleus
(also known as PAA2) are targeted to
the chloroplast and are required for
Current Biology
the delivery of Cu to the thylakoidal
protein plastocyanin, while only HMA6
is responsible for delivery of Cu to Figure 3. Copper homeostasis in mammals.
A generalized mammalian cell has similar Cu homeostasis machinery to yeast, with increased
stromal SOD. Plastocyanin is
complexity of components. Ctr1 is the predominant importer of Cu into mammalian cells. The
required for photosynthesis and, like Ccs and Sod1 chaperones are conserved from single cell eukaryotes. Atox1, the mammalian
cytochrome c oxidase, is involved in Atx1 homologue, is responsible for delivery of Cu to the two P-type ATPases in mammals,
electron flow. ATP7A and ATP7B. These two P-type ATPases are also important for delivery of Cu to the Golgi
The Arabidopsis CCH protein to load onto proteins and in distinct cell types, such as intestinal epithelial cells or hepatocytes,
harbors an ATX1-like metallochaperone to efflux Cu. MTF1 transcriptionally activates metallothionein genes (MTI/II) and other targets.
How Cu status is communicated between tissues must be explored to understand Cu home-
domain in its amino terminus, but has
ostasis throughout metazoan organisms.
a plant-specific coiled-coil
carboxy-terminal domain. This domain
forms amyloid-like fibrils and may pathogens. Indeed, Cu has been used that ATP7A may be responsible
play a role in CCH-mediated Cu as a bacteriocidal and fungicidal agent for the increased phagosomal Cu
transport through the plasmodesmata, for over a century, with a notable use concentrations observed during
representing a novel method of as the active ingredient in Bordeaux infection. This increased pool of
intercellular Cu movement and, mixture, which protects grapes from potentially toxic Cu in the lumen of the
perhaps, signaling. It is unclear fungal infection. This anti-microbial phagosome is not without impact on
how Cu is loaded into the xylem for activity of Cu seems to have been invading pathogens. Several reports
transport around the plant, although harnessed by eukaryotes, as there is demonstrate that bacterial cells
organic acids such as citrate, malate mounting evidence that innate immune upregulate expression of the Cu export
and oxalate, as well as phytochelatins cells use Cu as an anti-microbial ATPases during infection in a manner
(oligomers of glutathione, also found weapon. Studies have shown that dependent on Cu metalloregulatory
in some fungi) or nicotianimide may activated macrophages accumulate Cu transcription factors, suggesting that
function as Cu ligands in the vacuoles within the phagosome, the intracellular they mount a defense mechanism by
or xylem. compartment that captures and enhancing their ability to export Cu.
disables invading microbes. Moreover, In fact, M. tuberculosis has at least
Copper in infectious disease ATP7A protein levels are elevated two Cu-resistance operons, governed
A striking example of how Nature has in activated macrophages and the by two distinct Cu-responsive
evolved multiple uses for elements is protein re-localizes from the secretory transcription factors, underscoring the
the observation that, although Cu compartment to the phagosome, potential importance of Cu-resistance
is essential for many biological where there are parallel increases in mechanisms for a productive infection
processes, Cu is also a potent anti- phagosomal Cu levels. Taken together, by M. tuberculosis. This Cu increase
microbial weapon against invading these and other observations suggest in the phagosome would add to the
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protein effector, Xa13, that is proposed

to directly interact with the COPT1
and COPT5 Cu transporters, leading
to the redistribution of Cu out of the
Plasmodesmata xylem where X. oryzae replicates,
allowing pathogen dissemination. The
observations that bacterial pathogens
actively avoid intracellular Cu
accumulation or alter Cu distribution
Chloroplast in mammalian and plant hosts suggest
HMA8
that Cu status is a key battleground
(PAA2)
during infection.
CCH
Cu and human disease
Defects in Cu homeostasis lead to
HMA5 human disease. Wilson’s disease
Plastocyanin results from mutations in ATP7B,
leading to hepatic and neuronal
HMA6 Cu accumulation. Wilson’s disease
(PAA1) frequently leads to liver malfunction,
Sod1 neurological defects, including
COPT1
movement disorders, seizures, and
depression that is managed by low
Cu diets, chelation therapy or in
CCH ATX1
Sod1 extreme cases by liver transplant.
There is a potential link between
Cu and Parkinson’s disease as Cu
is associated with the accelerated
HMA7 COPT2
aggregation of the a-synuclein
(RAN1)
protein in the formation of Lewy
Ethylene bodies. Similarly, Cu has been
receptor
shown to promote the aggregation
of mutant Huntington’s disease
polyglutamine repeat proteins, as
COPT5 well as the neurotoxic oligomerization
of the amyloid-beta peptide in
the brains of Alzheimer’s disease
patients. Whether Cu dysregulation
SPL7
COPT1/2/CCH/miR398 Vacuole is a cause or a consequence of these
neurodegenerative diseases is under
Current Biology
Nucleus considerable investigation.
Menkes disease, caused by
Figure 4. Copper homeostasis in plants. mutations in the ATP7A gene,
Plants have expanded the number of encoded Cu homeostasis proteins. The COPT proteins results in peripheral Cu deficiency
are similar to the Ctr transporters found in mammals and yeast. COPT1 imports Cu and de- secondary to a failure in the
livers it to CCH. CCH, while similar to Atox1, has a carboxy-terminal extension that may be mobilization of dietary Cu
important for cell-to-cell transport of Cu between plasmodesmata. Plants also encode another
from intestinal enterocytes into
Atox1 homologue, ATX1, that is constitutively expressed. COPT5 has been associated with Cu
export from the vacuole during times of Cu starvation. Chloroplast-specific importers (PAA1 the circulation. As an
and PAA2) have also been identified and help to deliver Cu to important chloroplast-specific X-chromosome-linked recessive trait,
proteins, such as plastocyanin. RAN1 plays a similar role to Ccc2 by transporting Cu to the Menkes patients are typically male
Golgi to be loaded onto nascent proteins, such as the ethylene receptor. SPL7 is a Cu-respon- infants who present with seizure
sive transcriptional regulator that is responsible for activation and expression of CCH, COPT1, and profound neurological defects,
and COPT2, among other genes, as well as microRNAs that impact the expression of other
abnormal thermoregulation, connective
Cu-related genes, such as that encoding Cu, Zn SOD1.
tissue disorders, immune cell
armamentarium of the phagosome in plant–pathogen interactions. dysfunction and other symptoms that
that includes low pH, generation of Copper-containing amine oxidases, typically lead to mortality prior to three
reactive oxygen and nitrogen species, located around plant cell walls, utilize years of age. While some cases can
the elaboration of proteases and diamines and polyamines as substrates be partially ameliorated by intravenous
iron starvation to cope with invading to produce hydrogen peroxide which Cu administration, the blockade in Cu
pathogens. has microbicidal activity. Perhaps delivery across the blood–brain barrier
While evidence is mounting that in an attempt to counteract this and renders this lethal neurodegenerative
pathogenic microbes and their other host defense mechanisms, the disease largely refractile to parenteral
mammalian hosts do battle over Cu, rice bacterial pathogen Xanthomonas Cu supplementation. However, recent
this same dynamic may also occur oryzae expresses and secretes a exciting studies with a mouse model of
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Menkes disease suggest that horizontal (Figure 1A) that either

long-term rescue therapies might Correspondence moved perpendicular (‘up’ and to the
be developed by the delivery of a right, 20 degrees) to the lines (50% of
wild-type version of the ATP7A into trials) or oblique (‘down’ and to the
the ventricles of the brain. Changing right, –20 degrees) to the lines (in the

Concluding remarks
expectations other 50%), as we varied stimulus
contrast (high = 53% or low = 8%)
While iron and zinc have long been about speed alters and duration (133, 266 or 532 ms).
known as metal ions that are important Each session contained a short test
for life, it is clear that Cu is also a perceived motion block (216 trials), a long ‘training’
critical metal in biology. Given that
Cu is also a potentially dangerous direction block (720 trials) and a final test block
(216 trials). The test blocks were
toxin exploited by immune cells and always conducted with low stimulus
that Cu dysregulation causes human Grigorios Sotiropoulos1, speeds (4 deg/s). The training block
disease, the homeostasis of this metal Aaron R. Seitz2, and Peggy Seriès1 differed across groups, with a
ion must be under exquisite regulatory high-speed group performing the
control. Many questions remain to Our perceptions are fundamentally task with stimuli moving at 8 deg/s
be deciphered with respect to Cu’s altered by our knowledge of the (16 times the previously estimated
role in biology, including an articulation world. When cloud-gazing, for prior speed [1]) and a low-speed
of the entire constellation of example, we tend spontaneously group at 4 deg/s. We reasoned that
Cu-dependent processes, how hosts to recognize known objects in the exposure to such stimuli might lead
and microbes interact with respect to random configurations of evaporated the observers to implicitly update
Cu, how cells and organs distribute moisture. How our brains acquire their expectations towards faster
and communicate their Cu status, such knowledge and how it impacts speeds, leading to a decrease in the
and precisely how Cu dysregulation our perceptions is a matter of heated direction bias in all conditions, and
contributes to human disease. discussion. A topic of recent debate possibly a reversal of the illusion for
has concerned the hypothesis that the high speed group when tested
Further reading
Beaudoin, J., Ioannoni, R., Lopez-Maury, L., Bahler,
our visual system ‘assumes’ that with lower speeds (Figure 1B).
J., Ait-Mohand, S., Guérin, B., Dodani, S.C., objects are static or move slowly Consistent with previous findings
Chang, C.J., and Labbé, S. (2011). Mfc1 is a [1] rather than more quickly [1–3]. [4], we found that initial perception
novel forespore membrane copper transporter
in meiotic and sporulating cells. J. Biol. Chem. This hypothesis, or ‘prior on slow of motion direction was accurate
286, 34356–34372. speeds’, was postulated because for both groups at high contrast
Boal, A.K., and Rosenzweig, A.C. (2009). Structural
biology of copper trafficking. Chem. Rev. 109,
it could elegantly explain a number (see Figure S1 in the Supplemental
4760–4779. of perceptual biases observed Information), and biased towards
Donsante, A., Yi, L., Zerfas, P.M., Brinster, L.R., in situations of uncertainty [2]. perpendicular judgments at low
Sullivan, P., Goldstein, D.S., Prohaska, J.,
Centeno, J.A., Rushing, E., and Kaler, S.G. (2011). Interestingly, those biases affect contrast (Figure 1C). The low-speed
ATP7A gene addition to the choroid plexus not only the perception of speed, group showed a small within-session
results in long-term rescue of the lethal copper
transport defect in a Menkes disease mouse
but also the direction of motion. effect (p = 0.046, corresponding to
model. Mol. Ther. doi: 10.1038/mt.2011.143. For example, the direction of a the vertical displacement between
Kim, B.E., Nevitt, T., and Thiele, D.J. (2008). line whose endpoints are hidden dashed and solid lines in Figure
Mechanisms for copper acquisition, distribution
and regulation. Nat. Chem. Biol. 4, 176–185. (as in the ‘aperture problem’) or 1C); however, the illusion was
Lutsenko, S. (2010). Human copper homeostasis: poorly visible (for example, at low unaltered across sessions (p = 0.52).
a network of interconnected pathways. Curr.
Opin. Chem. Biol. 14, 211–217.
contrast or for short presentations) For the high-speed group, the
Nose, Y., Kim. B.E., and Thiele, D.J. (2006). Ctr1 drives is more often perceived as being initial perpendicular bias gradually
intestinal copper absorption and is essential for perpendicular to the line than it diminished until the illusion reversed
growth, iron metabolism, and neonatal cardiac
function. Cell Metab. 4, 235–244. really is — an illusion consistent with and the motion direction was most
Puig, S., Andres-Colas, N., Garcia-Molina, A., expecting that the line moves more often perceived as being more
and Penarrubia, L. (2007). Copper and iron
homeostasis in Arabidopsis: responses to metal
slowly than it really does. How this oblique. Interestingly, this group
deficiencies, interactions and biotechnological ‘prior on slow speeds’ is shaped by exhibited both a fast (within-session;
applications. Plant Cell Environ. 30, 271–290. experience and whether it remains p = 0.0047) and a slow
Ridge, P.G. Zhang, Y., and Gladyshev, V.N. (2008).
Comparative genomic analyses of copper malleable in adults is unclear. Here, (across-sessions; p < 0.001) learning
transporters and cuproproteomes reveal we show that systematic exposure component. The fast component is
evolutionary dynamics of copper utilization and
its link to oxygen. PLoS One 3, e1378.
to high-speed stimuli can lead to a type of perceptual adaptation in
Tottey, S., Harvie, D.R., and Robinson, N.J. (2005). a reversal of this direction illusion. which the perceptual system adapts
Understanding how cells allocate metals using This suggests that the shaping of to current perceptual conditions
metal sensors and metallochaperones. Acc.
Chem. Res. 38, 775–783. the brain’s prior expectations of (for example [5]) and then is reset.
White, C., Lee, J., Kambe, T., Fritsche, K., and even the most basic properties of The slow component resembles
Petris, M.J. (2009). A role for the ATP7A
copper-transporting ATPase in macrophage
the environment is a continuous perceptual learning, where the lack
bactericidal activity. J. Biol. Chem. 284, process. of a significant effect in the
33949–33956. We tested two groups of six low-speed group is consistent with
Department of Pharmacology and Cancer
participants, across five consecutive the need for a learning threshold to
Biology, Duke University School of Medicine, days, on their ability to report the be exceeded for perceptual learning
Durham, NC 27710, USA. motion direction of a field of parallel to occur [6]. These results provide
*E-mail: [email protected] lines oriented at 70 degrees from the first evidence that basic sensory