Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity

Eitan Hoch, Wei Lin, Jin Chai, Michal Hershfinkel, Dax Fu, Israel Sekler

Research output: Contribution to journalArticlepeer-review

108 Scopus citations


Zinc and cadmium are similar metal ions, but though Zn2+ is an essential nutrient, Cd2+ is a toxic and common pollutant linked to multiple disorders. Faster body turnover and ubiquitous distribution of Zn 2+ vs. Cd2+ suggest that a mammalian metal transporter distinguishes between these metal ions. We show that the mammalian metal transporters, ZnTs, mediate cytosolic and vesicular Zn2+ transport, but reject Cd2+, thus constituting the first mammalian metal transporter with a refined selectivity against Cd2+. Remarkably, the bacterial ZnT ortholog, YiiP, does not discriminate between Zn2+ and Cd2+. A phylogenetic comparison between the tetrahedral metal transport motif of YiiP and ZnTs identifies a histidine at the mammalian site that is critical for metal selectivity. Residue swapping at this position abolished metal selectivity of ZnTs, and fully reconstituted selective Zn 2+ transport of YiiP. Finally, we show that metal selectivity evolves through a reduction in binding but not the translocation of Cd2+ by the transporter. Thus, our results identify a unique class of mammalian transporters and the structural motif required to discriminate between Zn 2+ and Cd2+, and show that metal selectivity is tuned by a coordination-based mechanism that raises the thermodynamic barrier to Cd 2+ binding.

Original languageEnglish
Pages (from-to)7202-7207
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number19
StatePublished - 8 May 2012


  • Cd toxicity
  • Cd transport
  • Metal binding site
  • Zinc
  • Zn transporter

ASJC Scopus subject areas

  • General


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