pH-Dependent Coordination of Pb2+ to Metallothionein2: Structures and Insight into Lead Detoxification

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• 作者：Yonghui He ; Mengmeng Liu ; Narek Darabedian ; Yizeng Liang ; Deyin Wu ; Juan Xiang ; Feimeng Zhou
• 刊名：Inorganic Chemistry
• 出版年：2014
• 出版时间：March 17, 2014
• 年：2014
• 卷：53
• 期：6
• 页码：2822-2830
• 全文大小：441K
• 年卷期：v.53,no.6(March 17, 2014)
• ISSN：1520-510X

文摘

Lead is a toxic heavy metal whose detoxification in organisms is mainly carried out by its coordination with some metalloproteins such as metallothioneins (MTs). Two Pb鈥揗T complexes, named as Pb₇鈥揗T2(I) and Pb₇鈥揗T2(II), form under neutral and weakly acidic conditions, respectively. However, the structures of the two complexes, which are crucial for a better understanding of the detoxification mechanism of Pb鈥揗Ts, have not been clearly elucidated. In this Work, coordination of Pb²⁺ with rabbit liver apo鈥揗T2, as well as with the two individual domains (apo鈭捨盡T2 and apo鈭捨睲T2) at different pH, were studied by combined spectroscopic (UV鈥搗isible, circular dichroism, and NMR) and computational methods. The results showed that in Pb₇鈥揗T2(I) the Pb²⁺ coordination is in the trigonal pyramidal Pb鈥揝₃ mode, whereas the Pb₇鈥揗T2(II) complex contains mixed trigonal pyramidal Pb鈥揝₃, distorted trigonal pyramidal Pb鈥揝₂O₁, and distorted quadrilateral pyramidal Pb鈥揝₃O₁ modes. The O-donor ligand in Pb₇鈥揗T2(II) was identified as the carboxyl groups of the aspartic acid residues at positions 2 and 56. Our studies also revealed that Pb₇鈥揗T2(II) has a greater acid tolerance and coordination stability than Pb₇鈥揗T2(I), thereby retaining the Pb²⁺ coordination at acidic pH. The higher flexibility of Pb₇鈥揗T2(II) renders it more accessible to lysosomal proteolysis than Pb₇鈥揗T2(I). Similar spectral features were observed in the coordination of Pb²⁺ by human apo-MT2, suggesting a commonality among mammalian MT2s in the Pb²⁺ coordination chemistry.