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{{Infobox_gene}}
{{PBB_Controls
'''ATOX1''' is a [[copper]] metallochaperone [[protein]] that is encoded by the ''ATOX1'' [[gene]] in humans.<ref name="Klomp 1997"/><ref name="entrez"/> In [[mammal]]s, ATOX1 plays a key role in copper [[homeostasis]] as it delivers copper from the [[cytosol]] to transporters [[ATP7A]] and [[ATP7B]].<ref name="Bertini 2006"/><ref name="Banci 2013"/><ref name="Maret 2014"/> [[Homology (biology)#Sequence homology|Homologous]] proteins are found in a wide variety of [[eukaryote]]s, including ''[[Saccharomyces cerevisiae]]'' as ATX1, and all contain a [[Conserved sequence|conserved]] metal binding domain.<ref name="Bertini 2006"/><ref name="Boal 2009"/>
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== Function ==
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[[Image:Copper metabolism.png|thumb|left|upright=0.75||
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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.<ref name="Bertini 2006"/> 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 [[metalloprotein]]s. 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 [[Golgi apparatus|trans-Golgi network]] or [[Secretion#Secretion in eukaryotic cells|secretory vesicles]].<ref name="Bertini 2006"/><ref name="Banci 2013"/><ref name="Maret 2014"/> 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.<ref name="Bertini 2006"/>
In addition to the metallochaperone function, recent reports have characterized ATOX1 as a [[Cyclin#Subtypes|cyclin D1]] [[transcription factor]].<ref name="Banci 2013"/>
 
==Structure &  metal coordination==
 
[[File:ATOX1 Cu Coordination.png|thumb|left|upright=1.2|
ATOX1 copper coordination ]]
 
ATOX1 has a [[Ferredoxin fold|ferrodoxin]]-like βαββαβ fold and coordinates to Cu(I) via a MXCXXC binding [[Sequence motif|motif]] located in between the first β-sheet and α-helix.<ref name="Bertini 2006"/><ref name="Maret 2014"/> The metal binding motif is largely solvent exposed in [[Apoenzyme|Apo]]-ATOX1 and a [[Protein structure|conformational]] change is induced upon coordination to Cu(I).<ref name="Maret 2014"/><ref name="Boal 2009"/> Cu(I) is coordinated in a distorted linear geometry to sulfurs of [[cystine]] to form a [[Molecular geometry|bond angle]] of 120°.<ref name="Maret 2014"/> The overall -1 charge of the primary [[coordination sphere]] is stabilized through the [[Coordination sphere#Second coordination sphere|secondary coordination sphere]] that contains a proximal positively charged [[lysine]].<ref name="Maret 2014"/><ref name="Boal 2009"/> ATOX1 also binds Hg(II), Cd(II), Ag(I), and [[cisplatin]] via this motif, but a physiological role, if any, is not yet known.<ref name="Maret 2014"/>
 
== Metal transfer ==
 
[[File:ATX1 CCC2.gif|thumb|right|upright=1 | Model of ligand exchange copper transfer from Atx1 to Ccc2]]
 
ATOX1 transfers Cu(I) to transporters [[ATP7A]] and [[Wilson disease protein|ATP7B]].<ref name="Bertini 2006"/><ref name="Banci 2013"/><ref name="Maret 2014"/> Transfer occurs via a [[Ligand#Ligand exchange|ligand exchange]] mechanism, where Cu(I) transiently adopts a 3-coordinate geometry with cysteine ligands from ATOX1 and the associated transporter.<ref name="Maret 2014"/> The ligand exchange mechanism allows for faster exchange than a [[diffusion]] mechanism and imparts specificity for both the metal and transporter.<ref name="Robinson 2010"/> Since the ligand exchange accelerates that transfer and the reaction has a shallow thermodynamic gradient, it is said to be under [[Chemical kinetics|kinetic]] control rather than [[Thermodynamic free energy|thermodynamic]] control.<ref name="Maret 2014"/><ref name="Robinson 2010"/>
 
== Clinical significance ==
 
Although there are presently no known [[disease]]s 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.<ref name="Maret 2014"/>
* The mechanism of [[Ammonium tetrathiomolybdate#Uses|ammonium tetrathiomolybdate]] [NH<sub>4</sub>]<sub>2</sub>MoS<sub>4</sub> treatment of Wilson's Disease is under review. Since ATOX1 forms a stable complex tetrathiomolybdate, it is being studied as the potential therapeutic target.<ref name="Alvarez 2009"/><ref name="Dralle 2014"/>
 
== References ==
{{Reflist|33em|refs=
 
<ref name="Klomp 1997">{{cite journal | vauthors = Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD | title = Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis | journal = J Biol Chem | volume = 272 | issue = 14 | pages = 9221–6 | date = May 1997 | pmid = 9083055 | pmc =  | doi = 10.1074/jbc.272.14.9221 }}</ref>
 
<ref name="entrez">{{cite web | title = Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=475| accessdate = }}</ref>
 
<ref name="Bertini 2006">{{cite book|last1=Bertini|first1=I | first2 = H. B. | last2 = Gray | first3 =  E. I | last3 = Steifel | first4 = J. S. | last4 = Valentine |title=Biological Inorganic Chemistry, Structure and Reactivity|year=2006|publisher=University Science Books|isbn=1891389432 | name-list-format = vanc }}</ref>
 
<ref name="Banci 2013">{{cite book|last1=Banci|first1=Lucia|title=Metallomics and the cell|date=2013|publisher=Springer|location=Dordrecht|isbn=978-94-007-5561-1 | name-list-format = vanc }}</ref>
 
<ref name="Maret 2014">{{cite book|last1=Maret|first1=W. | first2 = A. | last2 = Wedd|title=Binding, transport and storage of metal ions in biological cells.|date=2014|publisher=Royal Soc Of Chemistry|location=[S.l.]|isbn=978-1-84973-599-5 | name-list-format = vanc }}</ref>
 
<ref name="Alvarez 2009">{{cite journal | vauthors = Alvarez HM, Xue Y, Robinson CD, Canalizo-Hernández MA, Marvin RG, Kelly RA, Mondragón A, Penner-Hahn JE, O'Halloran TV |author-link8=James Penner-Hahn | title = Tetrathiomolybdate inhibits copper trafficking proteins through metal cluster formation | journal = Science | volume = 327 | issue = 5963 | pages = 331–334 | date = Jan 2010 | pmid = 19965379 | doi = 10.1126/science.1179907 | pmc=3658115}}</ref>
 
<ref name="Dralle 2014">{{cite journal | vauthors = Mjos KD, Orvig C | title = Metallodrugs in medicinal inorganic chemistry | journal = Chemical Reviews | volume = 114 | issue = 8 | pages = 4540–4563 | date = Apr 2014 | pmid = 24456146 | doi = 10.1021/cr400460s }}</ref>
 
<ref name="Boal 2009">{{cite journal | vauthors = Boal AK, Rosenzweig AC | title = Structural biology of copper trafficking | journal = Chemical Reviews | volume = 109 | issue = 10 | pages = 4760–4779 | date = Oct 2009 | pmid = 19824702 | doi = 10.1021/cr900104z | pmc=2768115}}</ref>
 
<ref name="Robinson 2010">{{cite journal | vauthors = Robinson NJ, Winge DR | title = Copper metallochaperones | journal = Annual Review of Biochemistry | volume = 79 | issue = 1 | pages = 537–562 | date = 7 June 2010 | pmid = 20205585 | doi = 10.1146/annurev-biochem-030409-143539 | pmc = 3986808 }}</ref>


<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
{{GNF_Protein_box
| image = PBB_Protein_ATOX1_image.jpg
| image_source = [[Protein_Data_Bank|PDB]] rendering based on 1fe0.
| PDB = {{PDB2|1fe0}}, {{PDB2|1fe4}}, {{PDB2|1fee}}, {{PDB2|1tl4}}, {{PDB2|1tl5}}
| Name = ATX1 antioxidant protein 1 homolog (yeast)
| HGNCid = 798
| Symbol = ATOX1
| AltSymbols =; ATX1; HAH1; MGC138453; MGC138455
| OMIM = 602270
| ECnumber = 
| Homologene = 2984
| MGIid = 1333855
| GeneAtlas_image1 = PBB_GE_ATOX1_203454_s_at_tn.png
| Function = {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0016531 |text = copper chaperone activity}} {{GNF_GO|id=GO:0032767 |text = copper-dependent protein binding}} {{GNF_GO|id=GO:0046872 |text = metal ion binding}}
| Component = {{GNF_GO|id=GO:0005829 |text = cytosol}}
| Process = {{GNF_GO|id=GO:0006457 |text = protein folding}} {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0006825 |text = copper ion transport}} {{GNF_GO|id=GO:0006878 |text = cellular copper ion homeostasis}} {{GNF_GO|id=GO:0006979 |text = response to oxidative stress}} {{GNF_GO|id=GO:0030001 |text = metal ion transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 475
    | Hs_Ensembl = ENSG00000177556
    | Hs_RefseqProtein = NP_004036
    | Hs_RefseqmRNA = NM_004045
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 5
    | Hs_GenLoc_start = 151106079
    | Hs_GenLoc_end = 151111539
    | Hs_Uniprot = O00244
    | Mm_EntrezGene = 11927
    | Mm_Ensembl = ENSMUSG00000018585
    | Mm_RefseqmRNA = NM_009720
    | Mm_RefseqProtein = NP_033850
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 55293924
    | Mm_GenLoc_end = 55298385
    | Mm_Uniprot = Q5NCU2
  }}
}}
}}
'''ATX1 antioxidant protein 1 homolog (yeast)''', also known as '''ATOX1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=475| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
==External links==
{{PBB_Summary
* {{UCSC gene info|ATOX1}}
| section_title =  
| summary_text = This gene encodes a copper chaperone that plays a role in copper homeostasis by binding and transporting cytosolic copper to ATPase proteins in the trans-Golgi network for later incorporation to the ceruloplasmin. This protein also functions as an antioxidant against superoxide and hydrogen peroxide, and therefore, may play a significant role in cancer carcinogenesis. Because of its cytogenetic location, this gene represents a candidate gene for 5q-syndrome.<ref name="entrez">{{cite web | title = Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=475| accessdate = }}</ref>
}}


==References==
== Further reading ==
{{reflist|2}}
{{refbegin|33em}}
==Further reading==
* {{cite journal | vauthors = Hung IH, Casareno RL, Labesse G, Mathews FS, Gitlin JD | title = HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense. | journal = J. Biol. Chem. | volume = 273 | issue = 3 | pages = 1749–54 | year = 1998 | pmid = 9430722 | doi = 10.1074/jbc.273.3.1749 }}
{{refbegin | 2}}
* {{cite journal | vauthors = Larin D, Mekios C, Das K, Ross B, Yang AS, Gilliam TC | title = Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p. | journal = J. Biol. Chem. | volume = 274 | issue = 40 | pages = 28497–504 | year = 1999 | pmid = 10497213 | doi = 10.1074/jbc.274.40.28497 }}
{{PBB_Further_reading
* {{cite journal | vauthors = Hamza I, Schaefer M, Klomp LW, Gitlin JD | title = Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis. | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 23 | pages = 13363–8 | year = 1999 | pmid = 10557326 | pmc = 23953 | doi = 10.1073/pnas.96.23.13363 }}
| citations =
* {{cite journal | vauthors = Wernimont AK, Huffman DL, Lamb AL, O'Halloran TV, Rosenzweig AC | title = Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. | journal = Nat. Struct. Biol. | volume = 7 | issue = 9 | pages = 766–71 | year = 2000 | pmid = 10966647 | doi = 10.1038/78999 }}
*{{cite journal | author=Klomp LW, Lin SJ, Yuan DS, ''et al.'' |title=Identification and functional expression of HAH1, a novel human gene involved in copper homeostasis. |journal=J. Biol. Chem. |volume=272 |issue= 14 |pages= 9221-6 |year= 1997 |pmid= 9083055 |doi= }}
* {{cite journal | vauthors = Boultwood J, Strickson AJ, Jabs EW, Cheng JF, Fidler C, Wainscoat JS | title = 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. | journal = Hum. Genet. | volume = 106 | issue = 1 | pages = 127–9 | year = 2000 | pmid = 10982193 | doi = 10.1007/s004390051020 }}
*{{cite journal | author=Hung IH, Casareno RL, Labesse G, ''et al.'' |title=HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense. |journal=J. Biol. Chem. |volume=273 |issue= 3 |pages= 1749-54 |year= 1998 |pmid= 9430722 |doi= }}
* {{cite journal | vauthors = Walker JM, Tsivkovskii R, Lutsenko S | title = Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity. | journal = J. Biol. Chem. | volume = 277 | issue = 31 | pages = 27953–9 | year = 2002 | pmid = 12029094 | doi = 10.1074/jbc.M203845200 }}
*{{cite journal | author=Larin D, Mekios C, Das K, ''et al.'' |title=Characterization of the interaction between the Wilson and Menkes disease proteins and the cytoplasmic copper chaperone, HAH1p. |journal=J. Biol. Chem. |volume=274 |issue= 40 |pages= 28497-504 |year= 1999 |pmid= 10497213 |doi= }}
* {{cite journal | vauthors = Moore SD, Helmle KE, Prat LM, Cox DW | title = Tissue localization of the copper chaperone ATOX1 and its potential role in disease. | journal = Mamm. Genome | volume = 13 | issue = 10 | pages = 563–8 | year = 2003 | pmid = 12420134 | doi = 10.1007/s00335-002-2172-9 }}
*{{cite journal | author=Hamza I, Schaefer M, Klomp LW, Gitlin JD |title=Interaction of the copper chaperone HAH1 with the Wilson disease protein is essential for copper homeostasis. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 23 |pages= 13363-8 |year= 1999 |pmid= 10557326 |doi= }}
* {{cite journal | vauthors = Liu PC, Koeller DM, Kaler SG | title = Genomic organization of ATOX1, a human copper chaperone. | journal = BMC Genet. | volume = 4 | issue = | pages = 4 | year = 2004 | pmid = 12594858 | pmc = 150598 | doi = 10.1186/1471-2156-4-4 }}
*{{cite journal | author=Wernimont AK, Huffman DL, Lamb AL, ''et al.'' |title=Structural basis for copper transfer by the metallochaperone for the Menkes/Wilson disease proteins. |journal=Nat. Struct. Biol. |volume=7 |issue= 9 |pages= 766-71 |year= 2000 |pmid= 10966647 |doi= 10.1038/78999 }}
* {{cite journal | vauthors = Strausak D, Howie MK, Firth SD, Schlicksupp A, Pipkorn R, Multhaup G, Mercer JF | title = Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal binding sites of the Menkes protein. | journal = J. Biol. Chem. | volume = 278 | issue = 23 | pages = 20821–7 | year = 2003 | pmid = 12679332 | doi = 10.1074/jbc.M212437200 }}
*{{cite journal | author=Boultwood J, Strickson AJ, Jabs EW, ''et al.'' |title=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. |journal=Hum. Genet. |volume=106 |issue= 1 |pages= 127-9 |year= 2000 |pmid= 10982193 |doi= }}
* {{cite journal | vauthors = Ralle M, Lutsenko S, Blackburn NJ | title = 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. | journal = J. Biol. Chem. | volume = 278 | issue = 25 | pages = 23163–70 | year = 2003 | pmid = 12686548 | doi = 10.1074/jbc.M303474200 }}
*{{cite journal | author=Walker JM, Tsivkovskii R, Lutsenko S |title=Metallochaperone Atox1 transfers copper to the NH2-terminal domain of the Wilson's disease protein and regulates its catalytic activity. |journal=J. Biol. Chem. |volume=277 |issue= 31 |pages= 27953-9 |year= 2002 |pmid= 12029094 |doi= 10.1074/jbc.M203845200 }}
* {{cite journal | vauthors = Lutsenko S, Tsivkovskii R, Walker JM | title = Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1. | journal = Ann. N. Y. Acad. Sci. | volume = 986 | issue = | pages = 204–11 | year = 2003 | pmid = 12763797 | doi = 10.1111/j.1749-6632.2003.tb07161.x }}
*{{cite journal | author=Moore SD, Helmle KE, Prat LM, Cox DW |title=Tissue localization of the copper chaperone ATOX1 and its potential role in disease. |journal=Mamm. Genome |volume=13 |issue= 10 |pages= 563-8 |year= 2003 |pmid= 12420134 |doi= 10.1007/s00335-002-2172-9 }}
* {{cite journal | vauthors = Wernimont AK, Yatsunyk LA, Rosenzweig AC | title = Binding of copper(I) by the Wilson disease protein and its copper chaperone. | journal = J. Biol. Chem. | volume = 279 | issue = 13 | pages = 12269–76 | year = 2004 | pmid = 14709553 | doi = 10.1074/jbc.M311213200 }}
*{{cite journal | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{cite journal | vauthors = 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 | title = Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. | journal = Nat. Biotechnol. | volume = 22 | issue = 6 | pages = 707–16 | year = 2005 | pmid = 15146197 | doi = 10.1038/nbt971 }}
*{{cite journal | author=Liu PC, Koeller DM, Kaler SG |title=Genomic organization of ATOX1, a human copper chaperone. |journal=BMC Genet. |volume=4 |issue= |pages= 4 |year= 2004 |pmid= 12594858 |doi= }}
* {{cite journal | vauthors = Anastassopoulou I, Banci L, Bertini I, Cantini F, Katsari E, Rosato A | title = Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1. | journal = Biochemistry | volume = 43 | issue = 41 | pages = 13046–53 | year = 2004 | pmid = 15476398 | doi = 10.1021/bi0487591 }}
*{{cite journal | author=Strausak D, Howie MK, Firth SD, ''et al.'' |title=Kinetic analysis of the interaction of the copper chaperone Atox1 with the metal binding sites of the Menkes protein. |journal=J. Biol. Chem. |volume=278 |issue= 23 |pages= 20821-7 |year= 2003 |pmid= 12679332 |doi= 10.1074/jbc.M212437200 }}
* {{cite journal | vauthors = Banci L, Bertini I, Ciofi-Baffoni S, Chasapis CT, Hadjiliadis N, Rosato A | title = An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal-binding domains of the Menkes protein. | journal = FEBS J. | volume = 272 | issue = 3 | pages = 865–71 | year = 2005 | pmid = 15670166 | doi = 10.1111/j.1742-4658.2004.04526.x }}
*{{cite journal | author=Ralle M, Lutsenko S, Blackburn NJ |title=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. |journal=J. Biol. Chem. |volume=278 |issue= 25 |pages= 23163-70 |year= 2003 |pmid= 12686548 |doi= 10.1074/jbc.M303474200 }}
* {{cite journal | vauthors = Jeney V, Itoh S, Wendt M, Gradek Q, Ushio-Fukai M, Harrison DG, Fukai T | title = Role of antioxidant-1 in extracellular superoxide dismutase function and expression. | journal = Circ. Res. | volume = 96 | issue = 7 | pages = 723–9 | year = 2005 | pmid = 15761197 | doi = 10.1161/01.RES.0000162001.57896.66 }}
*{{cite journal | author=Lutsenko S, Tsivkovskii R, Walker JM |title=Functional properties of the human copper-transporting ATPase ATP7B (the Wilson's disease protein) and regulation by metallochaperone Atox1. |journal=Ann. N. Y. Acad. Sci. |volume=986 |issue= |pages= 204-11 |year= 2003 |pmid= 12763797 |doi= }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
*{{cite journal | author=Wernimont AK, Yatsunyk LA, Rosenzweig AC |title=Binding of copper(I) by the Wilson disease protein and its copper chaperone. |journal=J. Biol. Chem. |volume=279 |issue= 13 |pages= 12269-76 |year= 2004 |pmid= 14709553 |doi= 10.1074/jbc.M311213200 }}
*{{cite journal | author=Brandenberger R, Wei H, Zhang S, ''et al.'' |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707-16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 }}
*{{cite journal  | author=Anastassopoulou I, Banci L, Bertini I, ''et al.'' |title=Solution structure of the apo and copper(I)-loaded human metallochaperone HAH1. |journal=Biochemistry |volume=43 |issue= 41 |pages= 13046-53 |year= 2004 |pmid= 15476398 |doi= 10.1021/bi0487591 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Banci L, Bertini I, Ciofi-Baffoni S, ''et al.'' |title=An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal-binding domains of the Menkes protein. |journal=FEBS J. |volume=272 |issue= 3 |pages= 865-71 |year= 2005 |pmid= 15670166 |doi= 10.1111/j.1742-4658.2004.04526.x }}
*{{cite journal  | author=Jeney V, Itoh S, Wendt M, ''et al.'' |title=Role of antioxidant-1 in extracellular superoxide dismutase function and expression. |journal=Circ. Res. |volume=96 |issue= 7 |pages= 723-9 |year= 2005 |pmid= 15761197 |doi= 10.1161/01.RES.0000162001.57896.66 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
{{PDB Gallery|geneid=475}}
{{WikiDoc Sources}}
{{Metal metabolism}}
 
[[Category:Proteins]]

Latest revision as of 08:31, 16 May 2018

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
Wikidata
View/Edit Human

ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans.[1][2] In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B.[3][4][5] Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.[3][6]

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.[3] 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.[3][4][5] 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.[3] In addition to the metallochaperone function, recent reports have characterized ATOX1 as a cyclin D1 transcription factor.[4]

Structure & metal coordination

File:ATOX1 Cu Coordination.png
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.[3][5] The metal binding motif is largely solvent exposed in Apo-ATOX1 and a conformational change is induced upon coordination to Cu(I).[5][6] Cu(I) is coordinated in a distorted linear geometry to sulfurs of cystine to form a bond angle of 120°.[5] The overall -1 charge of the primary coordination sphere is stabilized through the secondary coordination sphere that contains a proximal positively charged lysine.[5][6] ATOX1 also binds Hg(II), Cd(II), Ag(I), and cisplatin via this motif, but a physiological role, if any, is not yet known.[5]

Metal transfer

File:ATX1 CCC2.gif
Model of ligand exchange copper transfer from Atx1 to Ccc2

ATOX1 transfers Cu(I) to transporters ATP7A and ATP7B.[3][4][5] 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.[5] The ligand exchange mechanism allows for faster exchange than a diffusion mechanism and imparts specificity for both the metal and transporter.[7] 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.[5][7]

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.[5]
  • 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.[8][9]

References

  1. ↑ 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.
  2. ↑ "Entrez Gene: ATOX1 ATX1 antioxidant protein 1 homolog (yeast)".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Bertini I, Gray HB, Steifel EI, Valentine JS (2006). Biological Inorganic Chemistry, Structure and Reactivity. University Science Books. ISBN 1891389432.
  4. ↑ 4.0 4.1 4.2 4.3 Banci L (2013). Metallomics and the cell. Dordrecht: Springer. ISBN 978-94-007-5561-1.
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 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.
  6. ↑ 6.0 6.1 6.2 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 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. doi:10.1126/science.1179907. PMC 3658115. PMID 19965379.
  9. ↑ Mjos KD, Orvig C (Apr 2014). "Metallodrugs in medicinal inorganic chemistry". Chemical Reviews. 114 (8): 4540–4563. doi:10.1021/cr400460s. PMID 24456146.

External links

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. doi:10.1074/jbc.273.3.1749. 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. doi:10.1074/jbc.274.40.28497. 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. doi:10.1073/pnas.96.23.13363. PMC 23953. 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. doi:10.1038/78999. PMID 10966647.
  • 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. 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. doi:10.1074/jbc.M203845200. 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. doi:10.1007/s00335-002-2172-9. PMID 12420134.
  • Liu PC, Koeller DM, Kaler SG (2004). "Genomic organization of ATOX1, a human copper chaperone". BMC Genet. 4: 4. doi:10.1186/1471-2156-4-4. PMC 150598. 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. doi:10.1074/jbc.M212437200. 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. doi:10.1074/jbc.M303474200. 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: 204–11. doi:10.1111/j.1749-6632.2003.tb07161.x. PMID 12763797.
  • 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. doi:10.1074/jbc.M311213200. 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. doi:10.1038/nbt971. PMID 15146197.
  • 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. 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. doi:10.1111/j.1742-4658.2004.04526.x. PMID 15670166.
  • 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. doi:10.1161/01.RES.0000162001.57896.66. PMID 15761197.
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