biostudies-literatureHoch ENIGMS NIH HHS7202-7https://www.ebi.ac.uk/biostudies/studies/S-EPMC3358884biostudies-literatureUnknown109(19)Zinc and cadmium are similar metal ions, but though Zn(2+) is an essential nutrient, Cd(2+) is a toxic and common pollutant linked to multiple disorders. Faster body turnover and ubiquitous distribution of Zn(2+) vs. Cd(2+) suggest that a mammalian metal transporter distinguishes between these metal ions. We show that the mammalian metal transporters, ZnTs, mediate cytosolic and vesicular Zn(2+) transport, but reject Cd(2+), thus constituting the first mammalian metal transporter with a refined selectivity against Cd(2+). Remarkably, the bacterial ZnT ortholog, YiiP, does not discriminate between Zn(2+) and Cd(2+). 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. ResProceedings of the National Academy of Sciences of the United States of AmericaHistidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity.PMC3358884R01 GM065137Fu DHoch ESekler ILin WChai JHershfinkel MfalseHistidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity.Zinc and cadmium are similar metal ions, but though Zn(2+) is an essential nutrient, Cd(2+) is a toxic and common pollutant linked to multiple disorders. Faster body turnover and ubiquitous distribution of Zn(2+) vs. Cd(2+) suggest that a mammalian metal transporter distinguishes between these metal ions. We show that the mammalian metal transporters, ZnTs, mediate cytosolic and vesicular Zn(2+) transport, but reject Cd(2+), thus constituting the first mammalian metal transporter with a refined selectivity against Cd(2+). Remarkably, the bacterial ZnT ortholog, YiiP, does not discriminate between Zn(2+) and Cd(2+). 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. Res2012-01-01T00:00:00Z2012 May2025-04-04T14:32:12.577Z2019-03-27T00:53:46ZS-EPMC33588842252935310.1073/pnas.1200362109