# ATOX1

## Overview
The ATOX1 gene encodes the antioxidant 1 copper chaperone protein, which is integral to copper homeostasis and cellular redox balance. This protein is categorized as a copper chaperone, facilitating the transport of copper ions to various cellular destinations, including copper-dependent enzymes such as ATP7A and ATP7B. These enzymes are vital for numerous physiological processes, including neurotransmitter biosynthesis and antioxidant defense (Hatori2016The; Hamza2003Essential). Beyond its role in copper transport, ATOX1 functions as a copper-dependent transcription factor, influencing cell proliferation and processes like wound healing and angiogenesis (Itoh2008Novel). The protein also contributes to antioxidant defense by interacting with other proteins to mitigate oxidative stress (Hatori2016The). ATOX1's interactions and functions underscore its significance in maintaining cellular health and its potential implications in diseases such as Wilson's disease and various cancers (Kumari2019Insilico; Xie2024Cuproptosisrelated).

## Structure
The human ATOX1 gene encodes a copper chaperone protein that plays a crucial role in copper homeostasis. The primary structure of ATOX1 consists of a 68-residue polypeptide chain, featuring a conserved metal-binding motif, Cys-X-X-Cys (CXXC), which is essential for copper coordination (RodriguezGranillo2008Structure; Hussain2008Conserved). The secondary structure of ATOX1 is characterized by a ferredoxin-like α/β-fold, comprising a βαββαβ arrangement (Perkal2020Cu(I) page 3 of 5; Xi2013Conserved page 0 of 4).

In its tertiary structure, ATOX1 adopts a compact fold that facilitates its function in copper binding and transfer. The protein's structure is stabilized by interactions involving key residues such as Met10, Thr11, and Lys60, which contribute to its stability and flexibility (RodriguezGranillo2009Differential). ATOX1 typically functions as a monomer, although it can form a dimeric state under certain conditions, such as when bound to zinc ions (Mangini2022Crystal).

Post-translational modifications, such as phosphorylation, can influence ATOX1's activity and interactions, although specific modifications are not detailed in the provided context. The protein's ability to bind copper and other metal ions is crucial for its role in cellular copper transport and homeostasis.

## Function
The ATOX1 gene encodes a copper chaperone protein that plays a critical role in maintaining copper homeostasis and redox balance in human cells. ATOX1 primarily functions by binding copper ions and facilitating their transport to the secretory pathway, where they are incorporated into copper-dependent enzymes such as ATP7A and ATP7B, which are crucial for various physiological processes (Hatori2016The; Hamza2003Essential). This transport is essential for the activation of enzymes involved in neurotransmitter biosynthesis, iron metabolism, and antioxidant defense (Hatori2016The).

In addition to its role in copper transport, ATOX1 acts as a copper-dependent transcription factor. It translocates to the nucleus in response to copper, where it binds to the cyclin D1 promoter, promoting cell proliferation (Itoh2008Novel). This nuclear function is linked to processes such as wound healing and angiogenesis (Itoh2008Novel).

ATOX1 also contributes to antioxidant defense by reducing reactive oxygen species levels and enhancing cell viability under stress conditions. It interacts with proteins like XRCC5 to protect against oxidative DNA damage, highlighting its role in cellular health maintenance (Hatori2016The).

## Clinical Significance
Mutations and altered expression of the ATOX1 gene have significant clinical implications. In Wilson's disease, a disorder characterized by impaired copper elimination, ATOX1 plays a role as a genetic modifier. A novel missense variant, p.(Gly14Ser), affects the interaction between ATOX1 and ATP7B, potentially influencing copper transfer and contributing to the disease's clinical heterogeneity (Kumari2019Insilico). 

In cancer, ATOX1 is implicated in the progression of several types. In diffuse large B-cell lymphoma (DLBCL), ATOX1 is upregulated and promotes cell proliferation by modulating the MAPK signaling pathway through copper transport. Knockdown of ATOX1 results in decreased cell proliferation and cell cycle arrest, suggesting its potential as a therapeutic target (Xie2024Cuproptosisrelated). In melanoma, particularly BRAF mutation-positive cases, ATOX1 is overexpressed and essential for MAPK pathway activation, correlating with poor survival outcomes. Targeting ATOX1 with inhibitors like DCAC50 shows promise in reducing melanoma cell growth (Kim2019Copper). 

In breast cancer, high ATOX1 expression is associated with worse disease-specific survival, particularly in early-stage and ER-positive subtypes, indicating its potential as a prognostic biomarker (Blockhuys2020Evaluation).

## Interactions
The ATOX1 protein is a copper chaperone that plays a crucial role in copper homeostasis by facilitating copper delivery to copper-transporting ATPases, specifically ATP7A and ATP7B. ATOX1 interacts with ATP7B, particularly with its domains 2 and 4, with the interaction with domain 4 being notably strong. This interaction is stabilized by copper ions bridging cysteine residues in the MXCXXC motif of the proteins (van2004Copperdependent). 

The p.(Gly14Ser) variant of ATOX1 affects its interaction with ATP7B by causing steric hindrance to a critical cysteine in ATP7B's metal-binding motif, which is essential for copper transfer (Kumari2019Insilico). ATOX1 also interacts with the Wilson disease protein (WD4), where it transfers copper through a mechanism involving the formation of a stable Cu-dependent heterocomplex (RodriguezGranillo2010CopperTransfer).

In addition to its role in copper transport, ATOX1 interacts with the Parkinson's disease protein α-synuclein (αSyn) in a copper-dependent manner. This interaction involves metal-binding sites and affects the dynamics of both proteins, with significant changes observed in the N-terminal region of αSyn (Horvath2019Interaction). ATOX1's interaction with αSyn is significant in the context of copper homeostasis and Parkinson's disease pathology (Horvath2019Interaction).


## References


[1. (RodriguezGranillo2009Differential) Agustina Rodriguez-Granillo and Pernilla Wittung-Stafshede. Differential roles of met10, thr11, and lys60 in structural dynamics of human copper chaperone atox1. Biochemistry, 48(5):960–972, January 2009. URL: http://dx.doi.org/10.1021/bi8018652, doi:10.1021/bi8018652. This article has 17 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/bi8018652)

[2. (van2004Copperdependent) Elisabeth M.W.M. van Dongen, Leo W.J. Klomp, and Maarten Merkx. Copper-dependent protein–protein interactions studied by yeast two-hybrid analysis. Biochemical and Biophysical Research Communications, 323(3):789–795, October 2004. URL: http://dx.doi.org/10.1016/j.bbrc.2004.08.160, doi:10.1016/j.bbrc.2004.08.160. This article has 46 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.bbrc.2004.08.160)

[3. (Perkal2020Cu(I) page 4 of 5) Ortal Perkal, Zena Qasem, Meital Turgeman, Renana Schwartz, Lada Gevorkyan-Airapetov, Matic Pavlin, Alessandra Magistrato, Dan Thomas Major, and Sharon Ruthstein. Cu(i) controls conformational states in human atox1 metallochaperone: an epr and multiscale simulation study. The Journal of Physical Chemistry B, 124(22):4399–4411, May 2020. URL: http://dx.doi.org/10.1021/acs.jpcb.0c01744, doi:10.1021/acs.jpcb.0c01744. This article has 13 citations.](https://doi.org/10.1021/acs.jpcb.0c01744)

[4. (Horvath2019Interaction) Istvan Horvath, Stéphanie Blockhuys, Darius Šulskis, Stellan Holgersson, Ranjeet Kumar, Björn M. Burmann, and Pernilla Wittung-Stafshede. Interaction between copper chaperone atox1 and parkinson’s disease protein α-synuclein includes metal-binding sites and occurs in living cells. ACS Chemical Neuroscience, 10(11):4659–4668, October 2019. URL: http://dx.doi.org/10.1021/acschemneuro.9b00476, doi:10.1021/acschemneuro.9b00476. This article has 22 citations and is from a peer-reviewed journal.](https://doi.org/10.1021/acschemneuro.9b00476)

[5. (Kumari2019Insilico) Niti Kumari, Aman Kumar, Amit Pal, Babu Ram Thapa, Manish Modi, and Rajendra Prasad. In-silico analysis of novel p.(gly14ser) variant of atox1 gene: plausible role in modulating atox1–atp7b interaction. Molecular Biology Reports, 46(3):3307–3313, April 2019. URL: http://dx.doi.org/10.1007/S11033-019-04791-X, doi:10.1007/s11033-019-04791-x. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/S11033-019-04791-X)

[6. (Itoh2008Novel) Shinichi Itoh, Ha Won Kim, Osamu Nakagawa, Kiyoshi Ozumi, Susan M. Lessner, Hiroki Aoki, Kamran Akram, Ronald D. McKinney, Masuko Ushio-Fukai, and Tohru Fukai. Novel role of antioxidant-1 (atox1) as a copper-dependent transcription factor involved in cell proliferation. Journal of Biological Chemistry, 283(14):9157–9167, April 2008. URL: http://dx.doi.org/10.1074/jbc.m709463200, doi:10.1074/jbc.m709463200. This article has 223 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m709463200)

[7. (Mangini2022Crystal) V. Mangini, B.D. Belviso, F. Arnesano, and R. Caliandro. Crystal structure of human copper chaperone atox1 bound to zinc ion by cxxc motif. April 2022. URL: http://dx.doi.org/10.2210/pdb7zc3/pdb, doi:10.2210/pdb7zc3/pdb. This article has 1 citations.](https://doi.org/10.2210/pdb7zc3/pdb)

[8. (Hatori2016The) Yuta Hatori and Svetlana Lutsenko. The role of copper chaperone atox1 in coupling redox homeostasis to intracellular copper distribution. Antioxidants, 5(3):25, July 2016. URL: http://dx.doi.org/10.3390/antiox5030025, doi:10.3390/antiox5030025. This article has 104 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/antiox5030025)

[9. (Kim2019Copper) Ye-Jin Kim, Gavin J Bond, Tiffany Tsang, Jessica M Posimo, Luca Busino, and Donita C Brady. Copper chaperone atox1 is required for mapk signaling and growth in braf mutation-positive melanoma. Metallomics, 11(8):1430–1440, July 2019. URL: http://dx.doi.org/10.1039/c9mt00042a, doi:10.1039/c9mt00042a. This article has 45 citations and is from a peer-reviewed journal.](https://doi.org/10.1039/c9mt00042a)

[10. (RodriguezGranillo2010CopperTransfer) Agustina Rodriguez-Granillo, Alejandro Crespo, Dario A. Estrin, and Pernilla Wittung-Stafshede. Copper-transfer mechanism from the human chaperone atox1 to a metal-binding domain of wilson disease protein. The Journal of Physical Chemistry B, 114(10):3698–3706, February 2010. URL: http://dx.doi.org/10.1021/jp911208z, doi:10.1021/jp911208z. This article has 41 citations.](https://doi.org/10.1021/jp911208z)

[11. (Xie2024Cuproptosisrelated) Junjie Xie, Zhixiong Shao, Changjie Li, Cheng Zeng, and Biao Xu. Cuproptosis-related gene <i>atox1</i> promotes mapk signaling and diffuse large b-cell lymphoma proliferation via modulating copper transport. Biomolecules and Biomedicine, July 2024. URL: http://dx.doi.org/10.17305/bb.2024.10536, doi:10.17305/bb.2024.10536. This article has 0 citations.](https://doi.org/10.17305/bb.2024.10536)

[12. (Hamza2003Essential) Iqbal Hamza, Joseph Prohaska, and Jonathan D. Gitlin. Essential role for atox1 in the copper-mediated intracellular trafficking of the menkes atpase. Proceedings of the National Academy of Sciences, 100(3):1215–1220, January 2003. URL: http://dx.doi.org/10.1073/pnas.0336230100, doi:10.1073/pnas.0336230100. This article has 153 citations.](https://doi.org/10.1073/pnas.0336230100)

[13. (Hussain2008Conserved) Faiza Hussain, John S. Olson, and Pernilla Wittung-Stafshede. Conserved residues modulate copper release in human copper chaperone atox1. Proceedings of the National Academy of Sciences, 105(32):11158–11163, August 2008. URL: http://dx.doi.org/10.1073/pnas.0802928105, doi:10.1073/pnas.0802928105. This article has 42 citations.](https://doi.org/10.1073/pnas.0802928105)

[14. (Blockhuys2020Evaluation) Stéphanie Blockhuys, Donita C. Brady, and Pernilla Wittung-Stafshede. Evaluation of copper chaperone atox1 as prognostic biomarker in breast cancer. Breast Cancer, 27(3):505–509, January 2020. URL: http://dx.doi.org/10.1007/s12282-019-01044-4, doi:10.1007/s12282-019-01044-4. This article has 30 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12282-019-01044-4)

[15. (RodriguezGranillo2008Structure) Agustina Rodriguez-Granillo and Pernilla Wittung-Stafshede. Structure and dynamics of cu(i) binding in copper chaperones atox1 and copz: a computer simulation study. The Journal of Physical Chemistry B, 112(15):4583–4593, March 2008. URL: http://dx.doi.org/10.1021/jp711787x, doi:10.1021/jp711787x. This article has 30 citations.](https://doi.org/10.1021/jp711787x)