Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2

Marie C. Franz, Jonai Pujol-Giménez, Nicolas Montalbetti, Miguel Fernandez-Tenorio, Timothy R DeGrado, Ernst Niggli, Michael F Romero, Matthias A. Hediger

Research output: Contribution to journalArticle

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Abstract

The human zinc transporter SLC39A2, also known as ZIP2, was shown to mediate zinc transport that could be inhibited at pH <7.0 and stimulated by HCO3 -, suggesting a Zn2+/HCO3 - cotransport mechanism [Gaither, L. A., and Eide, D. J. (2000) J. Biol. Chem. 275, 5560-5564]. In contrast, recent experiments in our laboratory indicated that the functional activity of ZIP2 increases at acidic pH [Franz, M. C., et al. (2014) J. Biomol. Screening 19, 909-916]. The study presented here was therefore designed to reexamine the findings about the pH dependence and to extend the functional characterization of ZIP2. Our current results show that ZIP2-mediated transport is modulated by extracellular pH but independent of the H+ driving force. Also, in our experiments, ZIP2-mediated transport is not modulated by extracellular HCO3 -. Moreover, a high extracellular [K+], which induces depolarization, inhibited ZIP2-mediated transport, indicating that the transport mechanism is voltage-dependent. We also show that ZIP2 mediates the uptake of Cd2+ (Km ∼ 1.57 μM) in a pH-dependent manner (KH+ ∼ 66 nM). Cd2+ transport is inhibited by extracellular [Zn2+] (IC50 ∼ 0.32 μM), [Cu2+] (IC50 ∼ 1.81 μM), and to a lesser extent [Co2+], but not by [Mn2+] or [Ba2+]. Fe2+ is not transported by ZIP2. Accordingly, the substrate selectivity of ZIP2 decreases in the following order: Zn2+ > Cd2+ ≥ Cu2+ > Co2+. Altogether, we propose that ZIP2 is a facilitated divalent metal ion transporter that can be modulated by extracellular pH and membrane potential. Given that ZIP2 expression has been reported in acidic environments [Desouki, M. M., et al. (2007) Mol. Cancer 6, 37; Inoue, Y., et al. (2014) J. Biol. Chem. 289, 21451-21462; Tao, Y. T., et al. (2013) Mol. Biol. Rep. 40, 4979-4984], we suggest that the herein described H+-mediated regulatory mechanism might be important for determining the velocity and direction of the transport process.

Original languageEnglish (US)
Pages (from-to)3976-3986
Number of pages11
JournalBiochemistry
Volume57
Issue number26
DOIs
StatePublished - Jul 3 2018

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Depolarization
Metal ions
Zinc
Screening
Experiments
Membranes
Inhibitory Concentration 50
Electric potential
Substrates
Membrane Potentials
zinc-binding protein
Metals
Ions
Direction compound
Neoplasms

ASJC Scopus subject areas

  • Biochemistry

Cite this

Franz, M. C., Pujol-Giménez, J., Montalbetti, N., Fernandez-Tenorio, M., DeGrado, T. R., Niggli, E., ... Hediger, M. A. (2018). Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2. Biochemistry, 57(26), 3976-3986. https://doi.org/10.1021/acs.biochem.8b00511

Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2. / Franz, Marie C.; Pujol-Giménez, Jonai; Montalbetti, Nicolas; Fernandez-Tenorio, Miguel; DeGrado, Timothy R; Niggli, Ernst; Romero, Michael F; Hediger, Matthias A.

In: Biochemistry, Vol. 57, No. 26, 03.07.2018, p. 3976-3986.

Research output: Contribution to journalArticle

Franz, MC, Pujol-Giménez, J, Montalbetti, N, Fernandez-Tenorio, M, DeGrado, TR, Niggli, E, Romero, MF & Hediger, MA 2018, 'Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2', Biochemistry, vol. 57, no. 26, pp. 3976-3986. https://doi.org/10.1021/acs.biochem.8b00511
Franz MC, Pujol-Giménez J, Montalbetti N, Fernandez-Tenorio M, DeGrado TR, Niggli E et al. Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2. Biochemistry. 2018 Jul 3;57(26):3976-3986. https://doi.org/10.1021/acs.biochem.8b00511
Franz, Marie C. ; Pujol-Giménez, Jonai ; Montalbetti, Nicolas ; Fernandez-Tenorio, Miguel ; DeGrado, Timothy R ; Niggli, Ernst ; Romero, Michael F ; Hediger, Matthias A. / Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2. In: Biochemistry. 2018 ; Vol. 57, No. 26. pp. 3976-3986.
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AU - DeGrado, Timothy R

AU - Niggli, Ernst

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N2 - The human zinc transporter SLC39A2, also known as ZIP2, was shown to mediate zinc transport that could be inhibited at pH <7.0 and stimulated by HCO3 -, suggesting a Zn2+/HCO3 - cotransport mechanism [Gaither, L. A., and Eide, D. J. (2000) J. Biol. Chem. 275, 5560-5564]. In contrast, recent experiments in our laboratory indicated that the functional activity of ZIP2 increases at acidic pH [Franz, M. C., et al. (2014) J. Biomol. Screening 19, 909-916]. The study presented here was therefore designed to reexamine the findings about the pH dependence and to extend the functional characterization of ZIP2. Our current results show that ZIP2-mediated transport is modulated by extracellular pH but independent of the H+ driving force. Also, in our experiments, ZIP2-mediated transport is not modulated by extracellular HCO3 -. Moreover, a high extracellular [K+], which induces depolarization, inhibited ZIP2-mediated transport, indicating that the transport mechanism is voltage-dependent. We also show that ZIP2 mediates the uptake of Cd2+ (Km ∼ 1.57 μM) in a pH-dependent manner (KH+ ∼ 66 nM). Cd2+ transport is inhibited by extracellular [Zn2+] (IC50 ∼ 0.32 μM), [Cu2+] (IC50 ∼ 1.81 μM), and to a lesser extent [Co2+], but not by [Mn2+] or [Ba2+]. Fe2+ is not transported by ZIP2. Accordingly, the substrate selectivity of ZIP2 decreases in the following order: Zn2+ > Cd2+ ≥ Cu2+ > Co2+. Altogether, we propose that ZIP2 is a facilitated divalent metal ion transporter that can be modulated by extracellular pH and membrane potential. Given that ZIP2 expression has been reported in acidic environments [Desouki, M. M., et al. (2007) Mol. Cancer 6, 37; Inoue, Y., et al. (2014) J. Biol. Chem. 289, 21451-21462; Tao, Y. T., et al. (2013) Mol. Biol. Rep. 40, 4979-4984], we suggest that the herein described H+-mediated regulatory mechanism might be important for determining the velocity and direction of the transport process.

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