Skip to main content
SpringerLink
Log in

Metals on the move: zinc ions in cellular regulation and in the coordination dynamics of zinc proteins

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

Homeostatic control maintains essential transition metal ions at characteristic cellular concentrations to support their physiological functions and to avoid adverse effects. Zinc is especially widely used as a catalytic or structural cofactor in about 3000 human zinc proteins. In addition, the homeostatic control of zinc in eukaryotic cells permits functions of zinc(II) ions in regulation and in paracrine and intracrine signaling. Zinc ions are released from proteins through ligand-centered reactions in zinc/thiolate coordination environments, and from stores in cellular organelles, where zinc transporters participate in zinc loading and release. Muffling reactions allow zinc ions to serve as signaling ions (second messengers) in the cytosol that is buffered to picomolar zinc ion concentrations at steady-state. Muffling includes zinc ion binding to metallothioneins, cellular translocations of metallothioneins, delivery of zinc ions to transporter proteins, and zinc ion fluxes through cellular membranes with the result of removing the additional zinc ions from the cytosol and restoring the steady-state. Targets of regulatory zinc ions are proteins with sites for transient zinc binding, such as membrane receptors, enzymes, protein–protein interactions, and sensor proteins that control gene expression. The generation, transmission, targets, and termination of zinc ion signals involve proteins that use coordination dynamics in the inner and outer ligand spheres to control metal ion association and dissociation. These new findings establish critically important functions of zinc ions and zinc metalloproteins in cellular control.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

ER:

Endoplasmic reticulum

ERK:

Extracellular signal-regulated kinase

IP3 :

Inositol 1,4,5-trisphosphate

MT:

Metallothionein

MTF-1:

Metal-response element (MRE)-binding transcription factor-1

ZnT:

Zinc transporter

References

  • Andreini C, Banci L, Bertini I, Rosato A (2006) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201

    Article  PubMed  CAS  Google Scholar 

  • Bozym RA, Thompson RB, Stoddard AK, Fierke CA (2006) Measuring picomolar intracellular exchangeable zinc in PC-12 cells using a ratiometric fluorescence biosensor. ACS Chem Biol 1:103–111

    Article  PubMed  CAS  Google Scholar 

  • Chimienti F, Favier A, Seve M (2005) ZnT-8, a pancreatic beta-cell-specific zinc transporter. Biometals 18:313–317

    Article  PubMed  CAS  Google Scholar 

  • Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, Kikuchi K, Holmes WR (2008) Insights into Zn2+ homeostasis in neurons from experimental and modeling studies. Am J Physiol Cell Physiol 294:C726–C742

    Article  PubMed  CAS  Google Scholar 

  • Colvin RA, Holmes WR, Fontaine CP, Maret W (2010) Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis. Metallomics 2:306–317

    Article  PubMed  CAS  Google Scholar 

  • Danscher G, Stoltenberg M (2005) Zinc-specific autometallographic in vivo selenium methods: tracing of zinc-enriched (ZEN) terminals, ZEN pathways, and pools of zinc ions in a multitude of other ZEN cells. J Histochem Cytochem 53:141–153

    Article  PubMed  CAS  Google Scholar 

  • Dunn MF (2005) Zinc-ligand interactions modulate assembly and stability of the insulin hexamer—a review. Biometals 18:295–303

    Article  PubMed  CAS  Google Scholar 

  • Frangioni JV, Beahm PH, Shifrin V, Jost CA, Neel BG (1992) The nontransmembrane tyrosine phosphatase PTP-1B localizes to the endoplasmic reticulum via its amino acid C-terminal sequence. Cell 68:545–560

    Article  PubMed  CAS  Google Scholar 

  • Frederickson CJ, Koh JY, Bush AI (2005) The neurobiology of zinc in health and disease. Nat Rev Neurosci 6:449–462

    Article  PubMed  CAS  Google Scholar 

  • Fu D (2011) Zinc transporter Yiip from Escherichia coli. In: Messerschmidt A, Bode W, Cygler M (eds) Handbook of Metalloproteins. Wiley, Chichester (in press)

  • Gundelfinger ED, Boeckers TM, Baron MK, Bowie JU (2006) A role for zinc in postsynaptic density assembly and plasticity? Trends Biochem Sci 31:366–373

    Article  PubMed  CAS  Google Scholar 

  • Günes C, Heuchel R, Georgiev O, Müller KH, Lichtlen P, Blüthmann H, Marino S, Aguzzi A, Schaffner W (1998) Embryonic lethality and liver degeneration in mice lacking the metal-response transcriptional activator MTF-1. EMBO J 17:2846–2854

    Article  PubMed  Google Scholar 

  • Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, Manning Fox JE, MacDonald PE, Chimienti F, Dai FF, Wheeler MB (2008) Investigation of transport mechanisms and regulation of inctracellular Zn2+ in pancreatic α-cells. J Biol Chem 283:10184–10197

    Article  PubMed  CAS  Google Scholar 

  • Haase H, Maret W (2003) Intracellular zinc fluctuations modulate protein tyrosine phosphatase activity in insulin/insulin-like growth factor-1 signaling. Exp Cell Res 291:289–298

    Article  PubMed  CAS  Google Scholar 

  • Haase H, Maret W (2010) The regulatory and signaling functions of zinc ions in human cellular physiology. In: Zalups R, Koropatnick J (eds) Cellular and molecular biology of metals. Taylor and Francis, London, pp 179–210

    Google Scholar 

  • Hogstrand C, Verbost PM, Wendelaar Bonga SE (1999) Inhibition of human Ca2+-ATPase by Zn2+. Toxicology 133:139–145

    Article  PubMed  CAS  Google Scholar 

  • Hogstrand C, Zheng D, Feeney G, Cunningham P, Kille P (2008) Zinc-controlled gene expression by metal-regulatory transcription factor 1 (MTF-1) in a model vertebrate, the zebrafish. Biochem Soc Trans 36:1252–1257

    Article  PubMed  CAS  Google Scholar 

  • Hogstrand C, Kille P, Nicholson RI, Taylor KM (2009) Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol Med 15:101–110

    Article  PubMed  CAS  Google Scholar 

  • Kaltenberg J, Plum LM, Ober-Blöbaum J, Hönscheid A, Rink L, Haase H (2010) Zinc signals promote IL-2-dependent proliferation of T-cells. Eur J Immunol 40:1496–1503

    Article  PubMed  CAS  Google Scholar 

  • Knipp M, Charnock JM, Garner CD, Vasak M (2001) Structural and functional characterization of the Zn(II) site in dimethylargininase-1 (DDAH-1) from bovine brain. J Biol Chem 276:40449–40456

    Article  PubMed  CAS  Google Scholar 

  • Krezel A, Maret W (2006) Zinc buffering capacity of a eukaryotic cell at physiological pZn. J Biol Inorg Chem 11:1049–1062

    Article  PubMed  CAS  Google Scholar 

  • Krezel A, Maret W (2007) The nanomolar and picomolar Zn(II) binding properties of metallothionein. J Am Chem Soc 129:10911–10921

    Article  PubMed  CAS  Google Scholar 

  • Krezel A, Maret W (2008) Thionein/Metallothionein control Zn(II) availability and the activity of enzymes. J Biol Inorg Chem 13:401–409

    Article  PubMed  CAS  Google Scholar 

  • Krezel A, Hao Q, Maret W (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 463:188–200

    Article  PubMed  CAS  Google Scholar 

  • Laity JH, Andrews GK (2007) Understanding the mechanism of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys 463:201–210

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Maret W (2008) Human metallothionein metallomics. J Anal At Spectrom 23:1055–1062

    Article  CAS  Google Scholar 

  • Li Y, Maret W (2009) Transient fluctuations of intracellular zinc ions in cell proliferation. Exp Cell Res 315:2463–2470

    Article  PubMed  CAS  Google Scholar 

  • Li Y, Hawkins BE, DeWitt DS, Prough DS, Maret W (2010) The relationship between transient zinc ion fluctuations and redox signaling in the pathways of secondary cellular injury: relevance to traumatic brain injury. Brain Res 1330:131–141

    Article  PubMed  CAS  Google Scholar 

  • Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29:153–176

    Article  PubMed  Google Scholar 

  • Lopez V, Kelleher SL (2009) Zinc transporter-2 (ZnT2) variants are localized to distinct subcellular compartments and functionally transport zinc. Biochem J 422:43–52

    Article  PubMed  CAS  Google Scholar 

  • Lu M, Chai J, Fu D (2009) Structural basis for autoregulation of the zinc transporter Yiip. Nat Struct Mol Biol 16:1063–1067

    Article  PubMed  CAS  Google Scholar 

  • Maret W (2001) Crosstalk of the group IIa and IIb metals calcium and zinc in cellular signaling. Proc Natl Acad Sci USA 98:12325–12327

    Article  PubMed  CAS  Google Scholar 

  • Maret W (2004) Protein interface zinc sites: a role of zinc in the supramolecular assembly of proteins and in transient protein-protein interactions. In: Messerschmidt A, Bode W, Cygler M (eds) Handbook of metalloproteins, vol 3. Wiley, Chichester, pp 432–441

    Google Scholar 

  • Maret W (2006) Zinc coordination environments in proteins as redox sensors and signal transducers. Antioxid Redox Signal 8:1419–1441

    Article  PubMed  CAS  Google Scholar 

  • Maret W (2009) Molecular aspects of human cellular zinc homeostasis: redox control of zinc potentials and zinc signals. Biometals 22:149–157

    Article  PubMed  CAS  Google Scholar 

  • Maret W (2010) Metalloproteomics, metalloproteomes, and the annotation of metalloproteins. Metallomics 2:117–125

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Li Y (2009) Coordination dynamics of zinc in proteins. Chem Rev 109:4682–4707

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Vallee BL (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci USA 95:3478–3482

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Larsen KS, Vallee BL (1997) Coordination dynamics of biological zinc “clusters” in metallothioneins and in the DNA-binding domain of the transcription factor Gal4. Proc Natl Acad Sci USA 94:2233–2237

    Article  PubMed  CAS  Google Scholar 

  • Maret W, Jacob C, Vallee BL, Fischer EH (1999) Inhibitory sites in enzymes: zinc removal and reactivation by thionein. Proc Natl Acad Sci USA 96:1936–1940

    Article  PubMed  CAS  Google Scholar 

  • Murgia C, Devirgilis C, Mancini E, Donadel G, Zalewski P, Perozzi G (2009) Diabetes-linked zinc transporter ZnT8 is a homodimeric protein expressed by distinct rodent endocrine cell types in the pancreas and other glands. Nutr Metab Cardiovasc Dis 19:431–439

    Article  PubMed  CAS  Google Scholar 

  • Paoletti P, Ascher P, Neyton J (1997) High-affinity zinc inhibition of NMDA NR1-NR2A receptors. J Neurosci 17:5711–5725

    PubMed  CAS  Google Scholar 

  • Paoletti P, Vergnano AM, Barbour B, Casado M (2009) Zinc at glutamatergic synapses. Neuroscience 158:126–136

    Article  PubMed  CAS  Google Scholar 

  • Peck EJ, Ray WJ (1971) Metal complexes of phosphoglucomutase in vivo. J Biol Chem 246:1160–1167

    PubMed  Google Scholar 

  • Ray WJ (1969) Role of bivalent cations in the phosphoglucomutase system. J Biol Chem 244:3740–3747

    PubMed  CAS  Google Scholar 

  • Sauer GR, Smith DM, Cahalane M, Wu LNY, Wuthier RE (2003) Intracellular zinc fluxes associated with apoptosis in growth plate chondrocytes. J Cell Biochem 88:954–969

    Article  PubMed  CAS  Google Scholar 

  • Sensi SL, Paoletti P, Bush AI, Sekler I (2009) Zinc physiology and pathophysiology of the CNS. Nat Rev Neurosci 10:780–791

    Article  PubMed  CAS  Google Scholar 

  • Sharir H, Zinger A, Nevo A, Sekler I, Hershfinkel M (2010) Zinc released from injured cells is acting via the Zn2+-sensing receptor, ZnR, to trigger signaling leading to epithelial repair. J Biol Chem 285:26097–26106

    Article  PubMed  CAS  Google Scholar 

  • Simons TJB (1991) Intracellular free zinc and zinc buffering in human red blood cells. J Membr Biol 123:63–71

    Article  PubMed  CAS  Google Scholar 

  • Stork CJ, Li YV (2010) Zinc release from thapsigargin/IP3-sensitive stores in cultured cortical neurons. J Mol Signal 5:5

    Article  PubMed  Google Scholar 

  • Taylor KM, Vichova P, Jordan P, Hiscox S, Hendley R, Nicholson R (2008) ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer cells. Endocrinology 149:4912–4920

    Article  PubMed  CAS  Google Scholar 

  • Thomas RC, Coles JA, Deitmer JW (1991) Homeostatic muffling. Nature 350:564

    Article  PubMed  CAS  Google Scholar 

  • Ueno S, Tsukamoto M, Hirano T, Kikuchi K, Yamada MK, Nishiyama N, Nagano T, Matsuki N, Ikegaya Y (2002) Mossy fiber Zn2+ spillover modulates heterosynaptic N-methyl-D-aspartate receptor activity in hippcocampal CA3 circuits. J Cell Biol 158:215–220

    Article  PubMed  CAS  Google Scholar 

  • Vinkenborg JL, Nicolson TJ, Bellomo EA, Koay MS, Rutter GA, Merkx M (2009) Genetically encoded FRET sensors to monitor intracellular Zn2+ homeostasis. Nat Methods 6:737–740

    Article  PubMed  CAS  Google Scholar 

  • Waldron KJ, Robinson N (2009) How do bacterial cells ensure that metalloproteins get the correct metal? Nat Rev Microbiol 6:25–35

    Article  Google Scholar 

  • Williams RJP (1984) Zinc: what is its role in biology? Endeavor 8:65–70

    Article  CAS  Google Scholar 

  • Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, Kurosaki T, Yamashita S, Tokunaga M, Nishida K, Hirano T (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. King’s College London, Diabetes and Nutritional Sciences Division, 150 Stamford Street, London, SE1 9NH, UK

    Wolfgang Maret

Authors
  1. Wolfgang Maret
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wolfgang Maret.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Maret, W. Metals on the move: zinc ions in cellular regulation and in the coordination dynamics of zinc proteins. Biometals 24, 411–418 (2011). https://doi.org/10.1007/s10534-010-9406-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-010-9406-1

Keywords

Search

Navigation