ATOX1

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

Function


ATOX1 is an abbreviation of the full name Antioxidant Protein 1. The is_associated_with::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 is_associated_with::cytoplasm of eukaryotes. 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 is_associated_with::in vivo, in order to protect cells from generation of is_associated_with::reactive oxygen species and mismetallation of is_associated_with::metalloproteins. As a metal trafficking protein, ATOX1 is responsible for shuttling copper from the is_associated_with::cytosol to ATPase transporters ATP7A and ATP7B that move copper to the trans-Golgi network or secretory vesicles. In is_associated_with::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 is_associated_with::ceruloplasmin, a ferroxidase required for iron metabolism, within the golgi apparatus. In addition to the metallochaperone function, recent reports have characterized ATOX1 as a cyclin D1 is_associated_with::transcription factor.

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

Metal transfer


ATOX1 transfers Cu(I) to transporters ATP7A and ATP7B. 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. The ligand exchange mechanism allows for faster exchange than a is_associated_with::diffusion mechanism and imparts specificity for both the metal and transporter. 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.

Clinical significance
Although there are presently no known is_associated_with::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.
 * 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.