Elucidating the H+ coupled Zn2+ transport mechanism of ZIP4; implications in acrodermatitis enteropathica

Eitan Hoch, Moshe Levy, Michal Hershfinkel, Israel Sekler

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish
Article number734
JournalInternational Journal of Molecular Sciences
Volume21
Issue number3
DOIs
StatePublished - 1 Feb 2020

Keywords

  • SLC39A
  • ZIP
  • ZIP structure function
  • ZRT-IRT-like proteins
  • Zinc Transporters
  • Zinc transport
  • ZnT

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint

Dive into the research topics of 'Elucidating the H+ coupled Zn2+ transport mechanism of ZIP4; implications in acrodermatitis enteropathica'. Together they form a unique fingerprint.

Cite this