Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity
Histidine pairing at the metal transport site of mammalian ZnT transporters controls Zn2+ over Cd2+ selectivity
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DOI：
10.1073/pnas.1200362109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Sekler, Israel
中科院分区：
文献类型：
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作者：
Hoch, Eitan;Lin, Wei;Sekler, Israel
锌和镉是类似的金属离子，但尽管锌是一种必需的营养素，但镉是一种与多种疾病有关的有毒和常见的污染物。更快的身体周转和无处不在的分布的Zn 2+与Cd 2+表明，哺乳动物的金属转运蛋白区分这些金属离子。我们发现，哺乳动物金属转运蛋白，ZnTs，介导胞质和囊泡的Zn 2+运输，但拒绝Cd 2+，从而构成了第一个哺乳动物金属转运蛋白与一个精致的对Cd 2+的选择性。值得注意的是，细菌ZnT直系同源物YiiP不能区分Zn 2+和Cd 2+。YiiP和ZnTs的四面体金属转运基序之间的系统发育比较确定了在哺乳动物位点的组氨酸，这对金属选择性至关重要。在这个位置的残基交换废除ZnTs的金属选择性，并完全重建选择性Zn2+运输YiiP。最后，我们表明，金属选择性的演变，通过减少结合，但不是转运的Cd2+。因此，我们的研究结果确定了一类独特的哺乳动物转运蛋白和所需的结构基序，以区分锌2+和镉2+，并表明，金属的选择性是由一个基于协调的机制，提高了热力学障碍镉2+结合。
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 Zn2+ 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 Zn2+ 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 Zn2+ and Cd2+, and show that metal selectivity is tuned by a coordination-based mechanism that raises the thermodynamic barrier to Cd2+ binding.