ATOX1 is an abbreviation of the full name Antioxidant Protein 1. The
nomenclature stems from initial characterization that showed that ATOX1 protected cells from reactive oxygen species. Since then, the primary role of ATOX1 has been established as a copper metallochaperone protein found in the
cytoplasm of eukaryotes.[7] A metallochaperone is an important protein that has metal trafficking and sequestration roles. As a metal sequestration protein, ATOX1 is capable of binding free metals in vivo, in order to protect cells from generation of
reactive oxygen species and mismetallation of
metalloproteins. As a metal trafficking protein, ATOX1 is responsible for shuttling copper from the
cytosol to ATPase transporters ATP7A and ATP7B that move copper to the
trans-Golgi network or
secretory vesicles.[7][8][9] In Saccharomyces cerevisiae, Atx1 delivers Cu(I) to a homologous transporter, Ccc2. The delivery of copper to ATPase transporters is vital for the subsequent insertion of copper into
ceruloplasmin, a ferroxidase required for iron metabolism, within the golgi apparatus.[7]
In addition to the metallochaperone function, recent reports have characterized ATOX1 as a
cyclin D1transcription factor.[8]
Structure & metal coordination
ATOX1 copper coordination
ATOX1 has a
ferrodoxin-like βαββαβ fold and coordinates to Cu(I) via a MXCXXC binding
motif located in between the first β-sheet and α-helix.[7][9] The metal binding motif is largely solvent exposed in
Apo-ATOX1 and a
conformational change is induced upon coordination to Cu(I).[9][10] Cu(I) is coordinated in a distorted linear geometry to sulfurs of
cystine to form a
bond angle of 120°.[9] The overall -1 charge of the primary
coordination sphere is stabilized through the
secondary coordination sphere that contains a proximal positively charged
lysine.[9][10] ATOX1 also binds Hg(II), Cd(II), Ag(I), and
cisplatin via this motif, but a physiological role, if any, is not yet known.[9]
Metal transfer
Model of ligand exchange copper transfer from Atx1 to Ccc2
ATOX1 transfers Cu(I) to transporters
ATP7A and
ATP7B.[7][8][9] Transfer occurs via a
ligand exchange mechanism, where Cu(I) transiently adopts a 3-coordinate geometry with cysteine ligands from ATOX1 and the associated transporter.[9] The ligand exchange mechanism allows for faster exchange than a
diffusion mechanism and imparts specificity for both the metal and transporter.[11] Since the ligand exchange accelerates that transfer and the reaction has a shallow thermodynamic gradient, it is said to be under
kinetic control rather than
thermodynamic control.[9][11]
Clinical significance
Although there are presently no known
diseases directly associated with ATOX1 malfunction, there is currently active research in a few areas:
There is a link between ATOX1 levels and sensitivity of cells for Pt-based drugs like cisplatin.[9]
The mechanism of
ammonium tetrathiomolybdate [NH42MoS4 treatment of Wilson's Disease is under review. Since ATOX1 forms a stable complex tetrathiomolybdate, it is being studied as the potential therapeutic target.[12][13]
^
abcdefgBertini I, Gray HB, Steifel EI, Valentine JS (2006). Biological Inorganic Chemistry, Structure and Reactivity. University Science Books.
ISBN978-1891389436.
^
abcdefghijkMaret W, Wedd A (2014). Binding, transport and storage of metal ions in biological cells. [S.l.]: Royal Soc Of Chemistry.
ISBN978-1-84973-599-5.
Wernimont AK, Huffman DL, Lamb AL, O'Halloran TV, Rosenzweig AC (2000). "Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins". Nat. Struct. Biol. 7 (9): 766–71.
doi:
10.1038/78999.
PMID10966647.
S2CID30817425.
Boultwood J, Strickson AJ, Jabs EW, Cheng JF, Fidler C, Wainscoat JS (2000). "Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene". Hum. Genet. 106 (1): 127–9.
doi:
10.1007/s004390051020.
PMID10982193.
Moore SD, Helmle KE, Prat LM, Cox DW (2003). "Tissue localization of the copper chaperone ATOX1 and its potential role in disease". Mamm. Genome. 13 (10): 563–8.
doi:
10.1007/s00335-002-2172-9.
PMID12420134.
S2CID19978302.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16.
doi:
10.1038/nbt971.
PMID15146197.
S2CID27764390.
Anastassopoulou I, Banci L, Bertini I, Cantini F, Katsari E, Rosato A (2004). "Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1". Biochemistry. 43 (41): 13046–53.
doi:
10.1021/bi0487591.
PMID15476398.
Banci L, Bertini I, Ciofi-Baffoni S, Chasapis CT, Hadjiliadis N, Rosato A (2005). "An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal-binding domains of the Menkes protein". FEBS J. 272 (3): 865–71.
doi:
10.1111/j.1742-4658.2004.04526.x.
PMID15670166.
S2CID1130281.
ATOX1 is an abbreviation of the full name Antioxidant Protein 1. The
nomenclature stems from initial characterization that showed that ATOX1 protected cells from reactive oxygen species. Since then, the primary role of ATOX1 has been established as a copper metallochaperone protein found in the
cytoplasm of eukaryotes.[7] A metallochaperone is an important protein that has metal trafficking and sequestration roles. As a metal sequestration protein, ATOX1 is capable of binding free metals in vivo, in order to protect cells from generation of
reactive oxygen species and mismetallation of
metalloproteins. As a metal trafficking protein, ATOX1 is responsible for shuttling copper from the
cytosol to ATPase transporters ATP7A and ATP7B that move copper to the
trans-Golgi network or
secretory vesicles.[7][8][9] In Saccharomyces cerevisiae, Atx1 delivers Cu(I) to a homologous transporter, Ccc2. The delivery of copper to ATPase transporters is vital for the subsequent insertion of copper into
ceruloplasmin, a ferroxidase required for iron metabolism, within the golgi apparatus.[7]
In addition to the metallochaperone function, recent reports have characterized ATOX1 as a
cyclin D1transcription factor.[8]
Structure & metal coordination
ATOX1 copper coordination
ATOX1 has a
ferrodoxin-like βαββαβ fold and coordinates to Cu(I) via a MXCXXC binding
motif located in between the first β-sheet and α-helix.[7][9] The metal binding motif is largely solvent exposed in
Apo-ATOX1 and a
conformational change is induced upon coordination to Cu(I).[9][10] Cu(I) is coordinated in a distorted linear geometry to sulfurs of
cystine to form a
bond angle of 120°.[9] The overall -1 charge of the primary
coordination sphere is stabilized through the
secondary coordination sphere that contains a proximal positively charged
lysine.[9][10] ATOX1 also binds Hg(II), Cd(II), Ag(I), and
cisplatin via this motif, but a physiological role, if any, is not yet known.[9]
Metal transfer
Model of ligand exchange copper transfer from Atx1 to Ccc2
ATOX1 transfers Cu(I) to transporters
ATP7A and
ATP7B.[7][8][9] Transfer occurs via a
ligand exchange mechanism, where Cu(I) transiently adopts a 3-coordinate geometry with cysteine ligands from ATOX1 and the associated transporter.[9] The ligand exchange mechanism allows for faster exchange than a
diffusion mechanism and imparts specificity for both the metal and transporter.[11] Since the ligand exchange accelerates that transfer and the reaction has a shallow thermodynamic gradient, it is said to be under
kinetic control rather than
thermodynamic control.[9][11]
Clinical significance
Although there are presently no known
diseases directly associated with ATOX1 malfunction, there is currently active research in a few areas:
There is a link between ATOX1 levels and sensitivity of cells for Pt-based drugs like cisplatin.[9]
The mechanism of
ammonium tetrathiomolybdate [NH42MoS4 treatment of Wilson's Disease is under review. Since ATOX1 forms a stable complex tetrathiomolybdate, it is being studied as the potential therapeutic target.[12][13]
^
abcdefgBertini I, Gray HB, Steifel EI, Valentine JS (2006). Biological Inorganic Chemistry, Structure and Reactivity. University Science Books.
ISBN978-1891389436.
^
abcdefghijkMaret W, Wedd A (2014). Binding, transport and storage of metal ions in biological cells. [S.l.]: Royal Soc Of Chemistry.
ISBN978-1-84973-599-5.
Wernimont AK, Huffman DL, Lamb AL, O'Halloran TV, Rosenzweig AC (2000). "Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins". Nat. Struct. Biol. 7 (9): 766–71.
doi:
10.1038/78999.
PMID10966647.
S2CID30817425.
Boultwood J, Strickson AJ, Jabs EW, Cheng JF, Fidler C, Wainscoat JS (2000). "Physical mapping of the human ATX1 homologue (HAH1) to the critical region of the 5q- syndrome within 5q32, and immediately adjacent to the SPARC gene". Hum. Genet. 106 (1): 127–9.
doi:
10.1007/s004390051020.
PMID10982193.
Moore SD, Helmle KE, Prat LM, Cox DW (2003). "Tissue localization of the copper chaperone ATOX1 and its potential role in disease". Mamm. Genome. 13 (10): 563–8.
doi:
10.1007/s00335-002-2172-9.
PMID12420134.
S2CID19978302.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (2005). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nat. Biotechnol. 22 (6): 707–16.
doi:
10.1038/nbt971.
PMID15146197.
S2CID27764390.
Anastassopoulou I, Banci L, Bertini I, Cantini F, Katsari E, Rosato A (2004). "Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1". Biochemistry. 43 (41): 13046–53.
doi:
10.1021/bi0487591.
PMID15476398.
Banci L, Bertini I, Ciofi-Baffoni S, Chasapis CT, Hadjiliadis N, Rosato A (2005). "An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal-binding domains of the Menkes protein". FEBS J. 272 (3): 865–71.
doi:
10.1111/j.1742-4658.2004.04526.x.
PMID15670166.
S2CID1130281.