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Open AccessArticle

Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica

Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
*
Author to whom correspondence should be addressed.
Current address: Jnana Therapeutics, 50 Northern Avenue, Boston, MA 02210, USA.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(3), 734; https://doi.org/10.3390/ijms21030734
Received: 6 November 2019 / Revised: 13 January 2020 / Accepted: 14 January 2020 / Published: 22 January 2020
(This article belongs to the Special Issue Zinc Biology 2019)
Cellular Zn2+ homeostasis is tightly regulated and primarily mediated by designated Zn2+ transport proteins, namely zinc transporters (ZnTs; SLC30) that shuttle Zn2+ efflux, and ZRT-IRT-like proteins (ZIPs; SLC39) that mediate Zn2+ influx. While the functional determinants of ZnT-mediated Zn2+ efflux are elucidated, those of ZIP transporters are lesser understood. Previous work has suggested three distinct molecular mechanisms: (I) HCO3 or (II) H+ coupled Zn2+ transport, or (III) a pH regulated electrodiffusional mode of transport. Here, using live-cell fluorescent imaging of Zn2+ and H+, in cells expressing ZIP4, we set out to interrogate its function. Intracellular pH changes or the presence of HCO3 failed to induce Zn2+ influx. In contrast, extracellular acidification stimulated ZIP4 dependent Zn2+ uptake. Furthermore, Zn2+ uptake was coupled to enhanced H+ influx in cells expressing ZIP4, thus indicating that ZIP4 is not acting as a pH regulated channel but rather as an H+ powered Zn2+ co-transporter. We further illustrate how this functional mechanism is affected by genetic variants in SLC39A4 that in turn lead to Acrodermatitis enteropathica, a rare condition of Zn2+ deficiency. View Full-Text
Keywords: ZRT-IRT-like proteins, ZIP; Zinc Transporters, ZnT; zinc transport; ZIP structure function; SLC39A ZRT-IRT-like proteins, ZIP; Zinc Transporters, ZnT; zinc transport; ZIP structure function; SLC39A
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MDPI and ACS Style

Hoch, E.; Levy, M.; Hershfinkel, M.; Sekler, I. Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica. Int. J. Mol. Sci. 2020, 21, 734. https://doi.org/10.3390/ijms21030734

AMA Style

Hoch E, Levy M, Hershfinkel M, Sekler I. Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica. International Journal of Molecular Sciences. 2020; 21(3):734. https://doi.org/10.3390/ijms21030734

Chicago/Turabian Style

Hoch, Eitan; Levy, Moshe; Hershfinkel, Michal; Sekler, Israel. 2020. "Elucidating the H+ Coupled Zn2+ Transport Mechanism of ZIP4; Implications in Acrodermatitis Enteropathica" Int. J. Mol. Sci. 21, no. 3: 734. https://doi.org/10.3390/ijms21030734

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