ReviewCellular multitasking: The dual role of human Cu-ATPases in cofactor delivery and intracellular copper balance☆
Section snippets
Structural features of human copper-transporting ATPases
Human Cu-ATPases are large polytopic membrane proteins (Fig. 1). Cu-ATPase ATP7A consists of 1500 residues (163,334 kDa; pI 5.94) and is glycosylated, which brings the apparent molecular weight of this protein to 175–180 kDa when it is analyzed on denaturing SDS gels. Human Cu-ATPase ATP7B is slightly smaller, consisting of 1465 residues (157,339 Kda, pI 6.29). ATP7B is not glycosylated and runs with the mobility corresponding to a protein of 165 kDa. At the protein level, ATP7A and ATP7B are
Transport mechanism and regulation of catalytic activity of human Cu-ATPases
ATP7A and ATP7B belong to the large family of P-type ATPases. Similarly to other members of this family, Cu-ATPase, use the energy of ATP hydrolysis to transport ions across membranes. Unlike many other members of the P-type ATPase family, Cu-ATPases do not generate ion gradients, at least not in a direct sense, since copper stays bound to proteins both in the cytosol and outside of the cell. The major steps of the catalytic cycle through which Cu-ATPases proceed while transporting copper have
Copper transfer by Atox1 and the role of Cu-ATPase individual metal-binding subdomains in this process
It is thought that human Cu-ATPases receive copper from a small cytosolic protein called Atox1 Deletion of the Atox1 gene in mice is associated with growth failure, skin laxity, and hypopigmentation [76], a phenotype resembling the copper deficiency due to ATP7A inactivation. The metabolic studies confirmed that Atox1−/− cells have impaired cellular copper efflux consistent with the disrupted copper delivery to Cu-ATPases. In is interesting that the copper-dependent trafficking of ATP7A from
Intracellular trafficking of ATP7A and ATP7B
Consequences of genetic inactivation of human Cu-ATPases indicate that they perform at least two major functions in a cell. Specifically, the Cu-ATPases deliver copper to the copper-dependent enzymes in the secretory pathway and maintain the intracellular concentration of copper in a cell by exporting excess of copper either into circulation for further distribution between tissues or into the bile for removal with feces. To mediate these functions Cu-ATPases traffic between cell compartments (
Cu-ATPases in various phyla
The presence of Cu-ATPases in all phyla and the dichotomization of P1B (heavy metal transporting) ATPase and other P-type ATPases before the division into eukaryotic and prokaryotic cells illustrate an early evolution origin of Cu-ATPases. The evidence of Cu metabolism is already seen in thermophiles, such as primitive sulphur-metabolizing archaea A. fulgidus and hyper-thermophilic bacterium T. maritime, a representative of a very deep branch of eubacteria. The exact functional role of
Conclusion
In recent years, there has been an explosion in identification of new members of the Cu-ATPase subfamily, and the list of these transporters is likely to grow. For most of these proteins, we have only initial data that point to their important functional role in the organism development and/or survival. The studies of structurally simpler members of the Cu-ATPase family, such as CopA, have already provided immensely useful information on the structure and mechanism of copper pumps. The analysis
References (126)
- et al.
Biochim. Biophys. Acta
(2006) - et al.
J. Nutr. Biochem.
(2004) - et al.
Acta Histochem.
(2005) - et al.
Arch. Biochem. Biophys.
(2000) - et al.
J. Biol. Chem.
(1998) - et al.
J. Nutr.
(2005) - et al.
Neuroscience
(2006) - et al.
Clin. Biochem.
(2005) - et al.
Curr. Opin. Plant Biol.
(2006) - et al.
J. Biol. Chem.
(2004)
ATP7B mediates vesicular sequestration of copper: insight into biliary copper excretion
Gastroenterology
J. Biol. Chem.
J. Biol. Chem.
Biochem. Biophys. Res. Commun.
Biochim. Biophys. Acta
J. Biol. Chem.
J. Biol. Chem.
Genomics
J. Inorg. Biochem.
Eur. J. Cell Biol.
Biochim. Biophys. Acta
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Biochem. Biophys. Res. Commun.
J. Biol. Chem.
FEBS Lett.
Am. J. Hum. Genet.
Gastroenterology
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
J. Biol. Chem.
Biochem. Biophys. Res. Commun.
J. Biol. Chem.
Biochim. Biophys. Acta
J. Biol. Chem.
J. Biol. Chem.
Gastroenterology
Gastroenterology
Gastroenterology
Arch. Biochem. Biophys.
FEMS Microbiol. Rev.
Biochem. Biophys. Res. Commun.
Biometals
Nat. Chem. Biol.
J. Bioenerg. Biomembr.
Endocrinology
Hum. Mol. Genet.
Cited by (175)
Structure and mechanism of the human copper transporting ATPases: Fitting the pieces into a moving puzzle
2024, Biochimica et Biophysica Acta - BiomembranesA novel peptide-based fluorescent probe with a large stokes shift for rapid and sequential detection of Cu<sup>2+</sup> and CN<sup>−</sup> in aqueous systems and live cells
2022, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyCitation Excerpt :As an essential trace element, copper plays an important role in human physiology and actively participates in various biological processes [1]. However, excessive levels of Cu2+ in the human body can damage organs such as the kidneys, heart and liver, leading to diseases such as anaemia, gastrointestinal disorders, Alzheimer’s prion, Parkinson’s disease, sacute kidney failure and ischemic heart disease [2–4]. Cyanide ions (CN−) is highly destructive to humans’ various organs and systems, so it is highly toxic to mammals [5–6].
At sixes and sevens: cryptic domain in the metal binding chain of the human copper transporter ATP7A
2021, Biophysical JournalFluorescent sensing film decorated with ratiometric probe for visual and recyclable monitoring of Cu<sup>2+</sup>
2021, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy
- ☆
This work has been supported by the National Institute of Health Grants R01 DK071865 to S.L.