Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc.
TL;DR: It is proposed that ZnT‐1 transports zinc out of cells and that its absence accounts for the increased sensitivity of mutant cells to zinc toxicity.
Abstract: A cDNA encoding a zinc transporter (ZnT-1) was isolated from a rat kidney cDNA expression library by complementation of a mutated, zinc-sensitive BHK cell line. This cDNA was used to isolate the homologous mouse ZnT-1 gene. The proteins predicted for these transporters contain six membrane-spanning domains, a large intracellular loop and a C-terminal tail. ZnT-1 is homologous to zinc and cobalt resistance genes of yeast. Immunocytochemistry with an antibody to a myc epitope added to the C-terminus of ZnT-1 revealed localization to the plasma membrane. Transformation of normal cells with a mutant ZnT-1 lacking the first membrane-spanning domain conferred zinc sensitivity on wild-type cells, suggesting that ZnT-1 functions as a multimer. Deletion of the first two membrane-spanning domains resulted in a non-functional molecule, whereas deletion of the C-terminal tail produced a toxic phenotype. Mutant cells have a slightly higher steady-state level of intracellular zinc and high basal expression of a zinc-dependent reporter gene compared with normal cells. Mutant cells have a lower turnover of 65Zn compared with normal cells or mutant cells transformed with ZnT-1. We propose that ZnT-1 transports zinc out of cells and that its absence accounts for the increased sensitivity of mutant cells to zinc toxicity.
Citations
More filters
TL;DR: A major unifying thread of the review is a consideration of how the changes occurring during and after ischemia conspire to produce damaging levels of free radicals and peroxynitrite to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process.
Abstract: This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...
2,960 citations
TL;DR: A broad overview of the evidence for an involvement of each mechanism in heavy metal detoxification and tolerance is provided.
Abstract: Heavy metals such as Cu and Zn are essential for normal plant growth, although elevated concentrations of both essential and non-essential metals can result in growth inhibition and toxicity symptoms. Plants possess a range of potential cellular mechanisms that may be involved in the detoxification of heavy metals and thus tolerance to metal stress. These include roles for the following: for mycorrhiza and for binding to cell wall and extracellular exudates; for reduced uptake or efflux pumping of metals at the plasma membrane; for chelation of metals in the cytosol by peptides such as phytochelatins; for the repair of stress-damaged proteins; and for the compartmentation of metals in the vacuole by tonoplast-located transporters. This review provides a broad overview of the evidence for an involvement of each mechanism in heavy metal detoxification and tolerance.
2,751 citations
TL;DR: This review describes the workings of known metal-resistance systems in microorganisms and the transport of the 17 most important (heavy metal) elements is compared.
Abstract: We are just beginning to understand the metabolism of heavy metals and to use their metabolic functions in biotechnology, although heavy metals comprise the major part of the elements in the periodic table. Because they can form complex compounds, some heavy metal ions are essential trace elements, but, essential or not, most heavy metals are toxic at higher concentrations. This review describes the workings of known metal-resistance systems in microorganisms. After an account of the basic principles of homoeostasis for all heavy-metal ions, the transport of the 17 most important (heavy metal) elements is compared.
2,342 citations
Cites background from "Cloning and functional characteriza..."
...ZnT1 detoxi®es zinc by eux across the cytoplasmic membrane (Palmiter and Findley 1995)....
[...]
...ZnT1 detoxi®es zinc by e ux across the cytoplasmic membrane (Palmiter and Findley 1995)....
[...]
TL;DR: The ability of zinc to be bound specifically within a range of tetrahedral sites appears to be responsible for the evolution of the wide range of zinc-stabilized structural domains now known to exist.
Abstract: Zinc ions are key structural components of a large number of proteins. The binding of zinc stabilizes the folded conformations of domains so that they may facilitate interactions between the proteins and other macromolecules such as DNA. The modular nature of some of these zinc-containing proteins has allowed the rational design of site-specific DNA binding proteins. The ability of zinc to be bound specifically within a range of tetrahedral sites appears to be responsible for the evolution of the side range of zinc-stabilized structural domains now known to exist. The lack of redox activity for the zinc ion and its binding and exchange kinetics also may be important in the use of zinc for specific functional roles.
1,801 citations
TL;DR: Parts of zinc biology of the immune system are explored and a biological basis for the altered host resistance to infections observed during zinc deficiency and supplementation is attempted.
1,488 citations
Cites background from "Cloning and functional characteriza..."
...Recently, zinc transporters and channels mediating both the inward and outward movement of zinc were isolated from mammalian cells (216, 217)....
[...]
References
More filters
01 Jan 1989
TL;DR: The Biological Significance of Zinc for Man: Problems and Prospects and putative Therapeutic Roles for Zinc are described.
Abstract: 1. Physiology of Zinc: General Aspects.- 2. An Introduction to the Biochemistry of Zinc.- 3. Intestinal Absorption of Zinc.- 4. Promoters and Antagonists of Zinc Absorption.- 5. Systemic Transport of Zinc.- 6. Systemic Interactions of Zinc.- 7. Biochemistry of Zinc in Cell Division and Tissue Growth.- 8. Zinc in Cell Division and Tissue Growth: Physiological Aspects.- 9. Biochemical Pathologies of Zinc Deficiency.- 10. Zinc and Iron in Free Radical Pathology and Cellular Control.- 11. Zinc Status and Food Intake.- 12. Zinc and Reproduction: Effects of Deficiency on Foetal and Postnatal Development.- 13. A Note on Zinc and Immunocompetence.- 14. Zinc and Behaviour.- 15. Neurobiology of Zinc.- 16. Zinc in Endocrine Function.- 17. Severe Zinc Deficiency.- 18. Mild Zinc Deficiency in Human Subjects.- 19. Putative Therapeutic Roles for Zinc.- 20. The Diagnosis of Zinc Deficiency.- 21. Human Zinc Requirements.- 22. Dietary Pattern and Zinc Supply.- 23. Zinc Excess.- 24. The Biological Significance of Zinc for Man: Problems and Prospects.
400 citations
Book•
31 Oct 1988
TL;DR: In this article, it was pointed out that current knowledge of the truly clinical aspects of zinc metabolism is too often confused with its effects in animals and that too many of the animal studies have involved severe and prolonged zinc deficiency or other exaggerated nutritional conditions that cannot be realistically applied in the clinical setting.
Abstract: In keeping with the etiology theme, it also became apparent that the clinical aspects needed to be strictly separated from the animal aspects of zinc metabolism, a separation that has never previously been attempted. Although this division, like the separation of primary from secondary zinc depletion, may be somewhat arbitrary, it is the author‘s impression that current knowledge of the truly clinical aspects of zinc metabolism is too often confused with its effects in animals. The two will frequently be similar, but not always. In this book, therefore, animal studies are considered in part 2 (Biochemistry. Only a handful of references to animal studies has been included in part 1 (Clinical). The purpose of this separation is to clearly distinguish animal from human, experimental from clinical. Too many of the animal studies have involved severe and prolonged zinc deficiency or other exaggerated nutritional conditions that cannot be realistically applied in the clinical setting. Furthermore, animal studies are mainly or primary (dietary) zinc depletion, whereas in humans, secondary zinc depletion is more prevalent and has a more diverse etiology.
89 citations