The Role of Copper Chaperone Atox1 in Coupling Redox Homeostasis to Intracellular Copper Distribution

Human antioxidant protein 1 (Atox1) is a small cytosolic protein with an essential role in copper homeostasis. Atox1 functions as a copper carrier facilitating copper transfer to the secretory pathway. This process is required for activation of copper dependent enzymes involved in neurotransmitter biosynthesis, iron efflux, neovascularization, wound healing, and regulation of blood pressure. Recently, new cellular roles for Atox1 have emerged. Changing levels of Atox1 were shown to modulate response to cancer therapies, contribute to inflammatory response, and protect cells against various oxidative stresses. It has also become apparent that the activity of Atox1 is tightly linked to the cellular redox status. In this review, we summarize biochemical information related to a dual role of Atox1 as a copper chaperone and an antioxidant. We discuss how these two activities could be linked and contribute to establishing the intracellular copper balance and functional identity of cells during differentiation.

• Publication year

  2016

• Venue

  Antioxidants

• Publication date

  2016-07-27

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.3390/antiox5030025PMID 27472369PMCID 5039574
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2016cited by this paper
• Direct structural evidence of protein redox regulation obtained by in-cell NMR.

  2016cited by this paper
• Longitudinal analytical approaches to genetic data

  2016cited by this paper
• Neuronal differentiation is associated with a redox-regulated increase of copper flow to the secretory pathway

  2016cited by this paper
• Elevated copper impairs hepatic nuclear receptor function in Wilson's disease.

  2015cited by this paper
• Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function

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• Loop recognition and copper-mediated disulfide reduction underpin metal site assembly of CuA in human cytochrome oxidase

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• Tat-antioxidant 1 protects against stress-induced hippocampal HT-22 cells death and attenuate ischaemic insult in animal model

  2015cited by this paper
• Inhibition of human copper trafficking by a small molecule significantly attenuates cancer cell proliferation.

  2015cited by this paper
• Whole Blood Transcriptional Profiling Reveals Deregulation of Oxidative and Antioxidative Defence Genes in Myelofibrosis and Related Neoplasms. Potential Implications of Downregulation of Nrf2 for Genomic Instability and Disease Progression

  2014cited by this paper
• Glutaredoxin1 protects neuronal cells from copper-induced toxicity

  2014cited by this paper
• Copper and Copper Proteins in Parkinson's Disease

  2014cited by this paper
• Redox sulfur chemistry of the copper chaperone Atox1 is regulated by the enzyme glutaredoxin 1, the reduction potential of the glutathione couple GSSG/2GSH and the availability of Cu(I).

  2014cited by this paper
• Atox1 Contains Positive Residues that Mediate Membrane Association and Aid Subsequent Copper Loading

  2013cited by this paper
• Hydrogen sulfide protects SH-SY5Y neuronal cells against d-galactose induced cell injury by suppression of advanced glycation end products formation and oxidative stress.

  2013cited by this paper
• Cellular glutathione plays a key role in copper uptake mediated by human copper transporter 1.

  2013cited by this paper
• Knockdown of copper chaperone antioxidant-1 by RNA interference inhibits copper-stimulated proliferation of non-small cell lung carcinoma cells

  2013cited by this paper
• Novel Role of Copper Transport Protein Antioxidant-1 in Neointimal Formation After Vascular Injury

  2013cited by this paper
• COX19 mediates the transduction of a mitochondrial redox signal from SCO1 that regulates ATP7A-mediated cellular copper efflux

  2013cited by this paper
• Redox properties of the disulfide bond of human Cu,Zn superoxide dismutase and the effects of human glutaredoxin 1.

  2012cited by this paper
• Functional Partnership of the Copper Export Machinery and Glutathione Balance in Human Cells*

  2012cited by this paper
• Regulation of copper transporters in human cells.

  2012cited by this paper
• Urinary Copper Elevation in a Mouse Model of Wilson's Disease Is a Regulated Process to Specifically Decrease the Hepatic Copper Load

  2012cited by this paper
• Role of Copper Transport Protein Antioxidant 1 in Angiotensin II–Induced Hypertension: A Key Regulator of Extracellular Superoxide Dismutase

  2012cited by this paper
• Human superoxide dismutase 1 (hSOD1) maturation through interaction with human copper chaperone for SOD1 (hCCS)

  2012cited by this paper
• Unification of the Copper(I) Binding Affinities of the Metallo-chaperones Atx1, Atox1, and Related Proteins

  2011influential reference
• Superoxide Dismutases: Role in Redox Signaling, Vascular Function, and Diseases

  2011cited by this paper
• ATP7A-related copper transport diseases—emerging concepts and future trends

  2011cited by this paper
• Crystal structure of a copper-transporting PIB-type ATPase

  2011cited by this paper
• A potential copper-regulatory role for cytosolic expression of the DNA repair protein XRCC5.

  2011cited by this paper
• Copper trafficking mechanism of CXXC-containing domains: insight from the pH-dependence of their Cu(I) affinities.

  2011cited by this paper
• Neurologic Wilson's disease

  2010cited by this paper
• Metabolic oxidation regulates embryonic stem cell differentiation

  2010cited by this paper
• Role of Glutaredoxin1 and Glutathione in Regulating the Activity of the Copper-transporting P-type ATPases, ATP7A and ATP7B*

  2010cited by this paper
• Wilson Disease at a Single Cell Level

  2010cited by this paper
• Human copper homeostasis: a network of interconnected pathways.

  2010cited by this paper
• Control of Alzheimer's Amyloid Beta Toxicity by the High Molecular Weight Immunophilin FKBP52 and Copper Homeostasis in Drosophila

  2010cited by this paper
• Affinity gradients drive copper to cellular destinations

  2010influential reference
• Peptidylgycine α‐amidating monooxygenase and copper: A gene–nutrient interaction critical to nervous system function

  2010cited by this paper
• Human copper transporters: mechanism, role in human diseases and therapeutic potential.

  2009cited by this paper
• Copper transport into the secretory pathway is regulated by oxygen in macrophages

  2009cited by this paper
• Lysine-60 in copper chaperone Atox1 plays an essential role in adduct formation with a target Wilson disease domain.

  2009cited by this paper
• Copper accumulation and compartmentalization in mouse fibroblast lacking metallothionein and copper chaperone, Atox1.

  2009cited by this paper
• Novel mechanism for regulation of extracellular SOD transcription and activity by copper: role of antioxidant-1.

  2009cited by this paper
• Three-dimensional structure of the human copper transporter hCTR1

  2009cited by this paper
• Novel Role of Antioxidant-1 (Atox1) as a Copper-dependent Transcription Factor Involved in Cell Proliferation*

  2008cited by this paper
• Cell-specific ATP7A transport sustains copper-dependent tyrosinase activity in melanosomes

  2008influential reference
• Mechanism of Cu+-transporting ATPases: Soluble Cu+ chaperones directly transfer Cu+ to transmembrane transport sites

  2008cited by this paper
• Conserved residues modulate copper release in human copper chaperone Atox1

  2008influential reference
• Redox compartmentalization in eukaryotic cells.

  2008cited by this paper
• Mitochondrial copper(I) transfer from Cox17 to Sco1 is coupled to electron transfer

  2008cited by this paper
• The Different Intermolecular Interactions of the Soluble Copper-binding Domains of the Menkes Protein, ATP7A*

  2007cited by this paper
• Domain Organization and Movements in Heavy Metal Ion Pumps

  2007cited by this paper
• High-Throughput Identification of Catalytic Redox-Active Cysteine Residues

  2007cited by this paper
• Copper-dependent interaction of glutaredoxin with the N termini of the copper-ATPases (ATP7A and ATP7B) defective in Menkes and Wilson diseases.

  2006cited by this paper
• Redox Control of Apoptosis: An Update

  2006cited by this paper
• Evidence for iron channeling in the Fet3p-Ftr1p high-affinity iron uptake complex in the yeast plasma membrane.

  2006cited by this paper
• Role of Antioxidant-1 in Extracellular Superoxide Dismutase Function and Expression

  2005influential reference
• Human-like rodent amyloid-beta-peptide determines Alzheimer pathology in aged wild-type Octodon degu.

  2005cited by this paper
• Superoxide Inhibits 4Fe-4S Cluster Enzymes Involved in Amino Acid Biosynthesis

  2004cited by this paper
• Biology, structure and mechanism of P-type ATPases

  2004cited by this paper
• Faculty Opinions recommendation of Superoxide inhibits 4Fe-4S cluster enzymes involved in amino acid biosynthesis. Cross-compartment protection by CuZn-superoxide dismutase.

  2004cited by this paper
• Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1.

  2004cited by this paper
• Mechanisms for activating Cu- and Zn-containing superoxide dismutase in the absence of the CCS Cu chaperone.

  2004cited by this paper
• Essential role for Atox1 in the copper-mediated intracellular trafficking of the Menkes ATPase

  2003cited by this paper
• Human Copper-Transporting ATPase ATP7B (The Wilson's Disease Protein): Biochemical Properties and Regulation

  2002cited by this paper
• Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells.

  2002cited by this paper
• Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.

  2002cited by this paper
• The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis

  2001cited by this paper
• Solution structure of the Cu(I) and apo forms of the yeast metallochaperone, Atx1.

  2001cited by this paper
• The Copper Transport Protein Atox1 Promotes Neuronal Survival*

  2000cited by this paper
• Structure-Function Analyses of the ATX1 Metallochaperone*

  1999influential reference
• Glutathione redox potential in response to differentiation and enzyme inducers.

  1999cited by this paper
• Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase.

  1999cited by this paper
• Crystal structure of the Atx1 metallochaperone protein at 1.02 A resolution.

  1999cited by this paper
• HAH1 Is a Copper-binding Protein with Distinct Amino Acid Residues Mediating Copper Homeostasis and Antioxidant Defense*

  1998cited by this paper
• A Role for the Saccharomyces cerevisiae ATX1 Gene in Copper Trafficking and Iron Transport*

  1997cited by this paper
• Survival factor-insensitive generation of reactive oxygen species induced by serum deprivation in neuronal cells.

  1996cited by this paper
• The ATX1 gene of Saccharomyces cerevisiae encodes a small metal homeostasis factor that protects cells against reactive oxygen toxicity.

  1995influential reference
• The sodium pump : structure mechanism, hormonal control and its role in disease

  1994cited by this paper
• Calcium binding to calmodulin and its globular domains.

  1991cited by this paper
• Binding of Cu(II) to non-prosthetic sites in ceruloplasmin and bovine serum albumin.

  1990cited by this paper
• Glutathione is present in high concentrations in cultured astrocytes but not in cultured neurons.

  1989cited by this paper

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