ATOX1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesATOX1, ATX1, HAH1, antioxidant 1 copper chaperone
External IDsOMIM: 602270 MGI: 1333855 HomoloGene: 2984 GeneCards: ATOX1
Orthologs
SpeciesHumanMouse
Entrez

475

11927

Ensembl

ENSG00000177556

ENSMUSG00000018585

UniProt

O00244

O08997

RefSeq (mRNA)

NM_004045

NM_009720

RefSeq (protein)

NP_004036

NP_033850

Location (UCSC)Chr 5: 151.74 – 151.77 MbChr 11: 55.34 – 55.35 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans.[5][6] In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B.[7][8][9] Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.[7][10]

Function

Schematic of copper homeostasis cell biology

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 D1 transcription 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 [NH4]2MoS4 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]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000177556 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000018585 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD (May 1997). "Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis". J Biol Chem. 272 (14): 9221–6. doi:10.1074/jbc.272.14.9221. PMID 9083055.
  6. ↑ "Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)".
  7. 1 2 3 4 5 6 7 Bertini I, Gray HB, Steifel EI, Valentine JS (2006). Biological Inorganic Chemistry, Structure and Reactivity. University Science Books. ISBN 978-1891389436.
  8. 1 2 3 4 Banci L (2013). Metallomics and the cell. Dordrecht: Springer. ISBN 978-94-007-5561-1.
  9. 1 2 3 4 5 6 7 8 9 10 11 Maret W, Wedd A (2014). Binding, transport and storage of metal ions in biological cells. [S.l.]: Royal Soc Of Chemistry. ISBN 978-1-84973-599-5.
  10. 1 2 3 Boal AK, Rosenzweig AC (Oct 2009). "Structural biology of copper trafficking". Chemical Reviews. 109 (10): 4760–4779. doi:10.1021/cr900104z. PMC 2768115. PMID 19824702.
  11. 1 2 Robinson NJ, Winge DR (7 June 2010). "Copper metallochaperones". Annual Review of Biochemistry. 79 (1): 537–562. doi:10.1146/annurev-biochem-030409-143539. PMC 3986808. PMID 20205585.
  12. ↑ Alvarez HM, Xue Y, Robinson CD, Canalizo-Hernández MA, Marvin RG, Kelly RA, Mondragón A, Penner-Hahn JE, O'Halloran TV (Jan 2010). "Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation". Science. 327 (5963): 331–334. Bibcode:2010Sci...327..331A. doi:10.1126/science.1179907. PMC 3658115. PMID 19965379.
  13. ↑ Mjos KD, Orvig C (Apr 2014). "Metallodrugs in medicinal inorganic chemistry". Chemical Reviews. 114 (8): 4540–4563. doi:10.1021/cr400460s. PMID 24456146.

Further reading

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