ATOX1
| ATOX1 | |||
|---|---|---|---|
Gene ontology | |||
| Molecular function | |||
| Cellular component | |||
| Biological process | |||
| Sources:Amigo / QuickGO | |||
Ensembl | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| UniProt | |||||||||
| RefSeq (mRNA) | |||||||||
| RefSeq (protein) | |||||||||
| Location (UCSC) | Chr 5: 151.74 – 151.77 Mb | Chr 11: 55.34 – 55.35 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
| View/Edit Human | View/Edit Mouse |
ATOX1 is a
Function
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 has a
Metal transfer
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
- ^ a b c GRCh38: Ensembl release 89: ENSG00000177556 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018585 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 9083055.
- ^ "Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)".
- ^ ISBN 978-1891389436.
- ^ ISBN 978-94-007-5561-1.
- ^ ISBN 978-1-84973-599-5.
- ^ PMID 19824702.
- ^ PMID 20205585.
- PMID 19965379.
- PMID 24456146.
External links
- Human ATOX1 genome location and ATOX1 gene details page in the UCSC Genome Browser.
Further reading
- Hung IH, Casareno RL, Labesse G, Mathews FS, Gitlin JD (1998). "HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense". J. Biol. Chem. 273 (3): 1749–54. PMID 9430722.
- Larin D, Mekios C, Das K, Ross B, Yang AS, Gilliam TC (1999). "Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p". J. Biol. Chem. 274 (40): 28497–504. PMID 10497213.
- Hamza I, Schaefer M, Klomp LW, Gitlin JD (1999). "Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis". Proc. Natl. Acad. Sci. U.S.A. 96 (23): 13363–8. PMID 10557326.
- 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. S2CID 30817425.
- 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. PMID 10982193.
- Walker JM, Tsivkovskii R, Lutsenko S (2002). "Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity". J. Biol. Chem. 277 (31): 27953–9. PMID 12029094.
- 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. S2CID 19978302.
- Liu PC, Koeller DM, Kaler SG (2004). "Genomic organization of ATOX1, a human copper chaperone". BMC Genet. 4: 4. PMID 12594858.
- Strausak D, Howie MK, Firth SD, Schlicksupp A, Pipkorn R, Multhaup G, Mercer JF (2003). "Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal binding sites of the Menkes protein". J. Biol. Chem. 278 (23): 20821–7. PMID 12679332.
- Ralle M, Lutsenko S, Blackburn NJ (2003). "X-ray absorption spectroscopy of the copper chaperone HAH1 reveals a linear two-coordinate Cu(I) center capable of adduct formation with exogenous thiols and phosphines". J. Biol. Chem. 278 (25): 23163–70. PMID 12686548.
- Lutsenko S, Tsivkovskii R, Walker JM (2003). "Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1". Ann. N. Y. Acad. Sci. 986 (1): 204–11. S2CID 39325916.
- Wernimont AK, Yatsunyk LA, Rosenzweig AC (2004). "Binding of copper(I) by the Wilson disease protein and its copper chaperone". J. Biol. Chem. 279 (13): 12269–76. PMID 14709553.
- 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. S2CID 27764390.
- 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. PMID 15476398.
- 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. S2CID 1130281.
- Jeney V, Itoh S, Wendt M, Gradek Q, Ushio-Fukai M, Harrison DG, Fukai T (2005). "Role of antioxidant-1 in extracellular superoxide dismutase function and expression". Circ. Res. 96 (7): 723–9. PMID 15761197.
PDB gallery | |
|---|---|
|
