Mammalian copper-transporting P-type ATPases, ATP7A and ATP7B: emerging roles

Centre for Cellular and Molecular Biology, School of Life and Environmental Sciences, Deakin University, 221 Burwood Highway, Burwood, Victoria 3125, Australia.
The international journal of biochemistry & cell biology (Impact Factor: 4.05). 11/2009; 42(2):206-9. DOI: 10.1016/j.biocel.2009.11.007
Source: PubMed


Copper (Cu) has a role in a diverse and increasing number of pathways, physiological and disease processes. These roles are testament to the fundamental importance of Cu in biology and the need to understand the mechanisms that regulate Cu homeostasis. The mammalian Cu-transporting P-type ATPases ATP7A and ATP7B are two key proteins that regulate the Cu status of the body. They transport Cu across cellular membranes for biosynthetic and protective functions, enabling Cu to fulfill its role as a catalytic and structural cofactor for many essential enzymes, and to prevent a toxic build-up of Cu inside cells. A variety of regulatory mechanisms operate at transcriptional and post-translational levels to ensure adequate Cu supplies for both physiological and pathophysiological processes. This review summarizes the recent literature that is revealing the emerging roles of the Cu-ATPases in health and disease.

Download full-text


Available from: Julian Francis Mercer, Nov 18, 2014
22 Reads
  • Source
    • "ATP7A and ATP7B contribute to the maintenance of copper-dependent enzyme activity by delivering copper to the lumen of the secretory pathway in the trans-Golgi network, where copper metalation generates active cuproenzymes. These ATPases can also contribute to the maintenance of intracellular copper concentrations by transporting copper into secretory vesicles from the trans-Golgi network, which shuttle to the plasma membrane for copper excretion [76]. Here we found that, in diabetic LV, protein levels of both ATOX1 and ATP7B were decreased, consistent with possible impairment of copper supply for activation of cuproenzymes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Heart disease is the leading cause of death in diabetic patients, and defective copper metabolism may play important roles in the pathogenesis of diabetic cardiomyopathy (DCM). The present study sought to determine how myocardial copper status and key copper-proteins might become impaired by diabetes, and how they respond to treatment with the Cu (II)-selective chelator triethylenetetramine (TETA) in DCM. Methods Experiments were performed in Wistar rats with streptozotocin (STZ)-induced diabetes with or without TETA treatment. Cardiac function was analyzed in isolated-perfused working hearts, and myocardial total copper content measured by particle-induced x-ray emission spectroscopy (PIXE) coupled with Rutherford backscattering spectrometry (RBS). Quantitative expression (mRNA and protein) and/or activity of key proteins that mediate LV-tissue-copper binding and transport, were analyzed by combined RT-qPCR, western blotting, immunofluorescence microscopy, and enzyme activity assays. Statistical analysis was performed using Student’s t-tests or ANOVA and p-values of < 0.05 have been considered significant. Results Left-ventricular (LV) copper levels and function were severely depressed in rats following 16-weeks’ diabetes, but both were unexpectedly normalized 8-weeks after treatment with TETA was instituted. Localized myocardial copper deficiency was accompanied by decreased expression and increased polymerization of the copper-responsive transition-metal-binding metallothionein proteins (MT1/MT2), consistent with impaired anti-oxidant defences and elevated susceptibility to pro-oxidant stress. Levels of the high-affinity copper transporter-1 (CTR1) were depressed in diabetes, consistent with impaired membrane copper uptake, and were not modified by TETA which, contrastingly, renormalized myocardial copper and increased levels and cell-membrane localization of the low-affinity copper transporter-2 (CTR2). Diabetes also lowered indexes of intracellular (IC) copper delivery via the copper chaperone for superoxide dismutase (CCS) to its target cuproenzyme, superoxide dismutase-1 (SOD1): this pathway was rectified by TETA treatment, which normalized SOD1 activity with consequent bolstering of anti-oxidant defenses. Furthermore, diabetes depressed levels of additional intracellular copper-transporting proteins, including antioxidant-protein-1 (ATOX1) and copper-transporting-ATPase-2 (ATP7B), whereas TETA elevated copper-transporting-ATPase-1 (ATP7A). Conclusions Myocardial copper deficiency and defective cellular copper transport/trafficking are revealed as key molecular defects underlying LV impairment in diabetes, and TETA-mediated restoration of copper regulation provides a potential new class of therapeutic molecules for DCM.
    Cardiovascular Diabetology 06/2014; 13(1):100. DOI:10.1186/1475-2840-13-100 · 4.02 Impact Factor
  • Source
    • "In humans, the absorbed Cu is distributed inside the enterocyte, thus reaching the ATP7, which is a Cu-ATPase involved in Cu exportation from the cell. It is interesting to note that ATP7A expression occurs in most tissues while ATP7B expression is restricted to some tissues such as the small intestine (Lutsenko et al., 2007; Lönnerdal, 2008; La Fontaine et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Copper (Cu) accumulation and regulation of key-genes involved in Cu homeostasis were evaluated in freshwater- and saltwater-acclimated guppies Poecilia vivipara. Fish were exposed (96h) to environmentally relevant concentrations of dissolved Cu (0, 5.0, 9.0 and 20.0μg/L). In freshwater guppies, gill and liver Cu accumulation was dependent on Cu concentration in the exposure medium. In saltwater guppies, this dependence was observed only in the gut. These findings indicate that Cu accumulation was salinity- and tissue-dependent. Key genes involved in Cu metabolism were sequenced for the first time in P. vivipara. Transcripts coding for the high-affinity copper transporter (CTR1) and copper-transporting ATPase (ATP7B) were identified using polymerase chain reaction (PCR) and gene sequencing. The full-length CTR1 open reading frame (1560bp) and a partial ATP7B (690bp) were discovered. Predicted amino acid sequences shared high identities with the CTR1 of Fundulus heteroclitus (81%) and the ATP7B of Sparus aurata (87%). Basal transcriptional levels addressed by RT-qPCR in control fish indicate that CTR1 and ATP7B was highly transcribed in liver of freshwater guppies while CTR1 was highly transcribed in gut of saltwater guppies. This could explain the higher Cu accumulation observed in liver of freshwater guppies and in gut of saltwater guppies, because CTR1 is involved in Cu uptake. Reduced gill mRNA expression of CTR1 was observed in freshwater guppies exposed to 20.0μg/L Cu and in saltwater guppies exposed to 5.0μg/L Cu. In turn, reduced mRNA expression of gut ATP7B was observed in freshwater and salt water guppies exposed to 9.0 and 20.0μg/L Cu. Liver CTR1 and ATP7B transcription were not affected by Cu exposure. These findings suggest that gill CTR1 and gut ATP7B are down-regulated to limit Cu absorption after exposure to dissolved Cu, while liver CTR1 and ATP7B levels are maintained to allow Cu storage and detoxification. In conclusion, findings reported here indicate that Cu accumulation in the euryhaline guppy P. vivipara is tissue specific and dependent on water salinity. They also suggest that Cu homeostasis involves a differential transcriptional regulation of the newly identified Cu transporters, CTR1 and ATP7B.
    Aquatic toxicology (Amsterdam, Netherlands) 05/2014; 152C:300-307. DOI:10.1016/j.aquatox.2014.04.024 · 3.45 Impact Factor
  • Source
    • "Consistent with this finding, low-density lipoprotein (LDL) oxidation by macrophage-like THP-1 cells was found to be ATP7A-dependent, suggesting metal catalyzed oxidation by secreted copper ions (Qin et al., 2010). ATP7A is expressed in a broad range of both myeloid and non-myeloid cell types (La Fontaine et al., 2010; Wang et al., 2011), raising the possibility that a variety of cell types may similarly direct the copper payloads to kill internalized bacteria. These observations suggest a specific functional rationale for the array of mammalian copper transport genes upregulated by proinflammatory stimuli such as interferon-gamma and lipopolysaccharide and for the altered copper physiology noted above in section Copper as a Fenton Reagent. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent findings suggest that both host and pathogen manipulate copper content in infected host niches during infections. In this review, we summarize recent developments that implicate copper resistance as an important determinant of bacterial fitness at the host-pathogen interface. An essential mammalian nutrient, copper cycles between copper (I) (Cu(+)) in its reduced form and copper (II) (Cu(2+)) in its oxidized form under physiologic conditions. Cu(+) is significantly more bactericidal than Cu(2+) due to its ability to freely penetrate bacterial membranes and inactivate intracellular iron-sulfur clusters. Copper ions can also catalyze reactive oxygen species (ROS) generation, which may further contribute to their toxicity. Transporters, chaperones, redox proteins, receptors and transcription factors and even siderophores affect copper accumulation and distribution in both pathogenic microbes and their human hosts. This review will briefly cover evidence for copper as a mammalian antibacterial effector, the possible reasons for this toxicity, and pathogenic resistance mechanisms directed against it.
    Frontiers in Cellular and Infection Microbiology 02/2014; 4:3. DOI:10.3389/fcimb.2014.00003 · 3.72 Impact Factor
Show more