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

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journal contribution
posted on 17.12.2015 by Yonghui He, Mengmeng Liu, Narek Darabedian, Yizeng Liang, Deyin Wu, Juan Xiang, Feimeng Zhou
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–MT complexes, named as Pb7–MT2­(I) and Pb7–MT2­(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–MTs, have not been clearly elucidated. In this Work, coordination of Pb2+ with rabbit liver apo–MT2, as well as with the two individual domains (apo−αMT2 and apo−βMT2) at different pH, were studied by combined spectroscopic (UV–visible, circular dichroism, and NMR) and computational methods. The results showed that in Pb7–MT2­(I) the Pb2+ coordination is in the trigonal pyramidal Pb–S3 mode, whereas the Pb7–MT2­(II) complex contains mixed trigonal pyramidal Pb–S3, distorted trigonal pyramidal Pb–S2O1, and distorted quadrilateral pyramidal Pb–S3O1 modes. The O-donor ligand in Pb7–MT2­(II) was identified as the carboxyl groups of the aspartic acid residues at positions 2 and 56. Our studies also revealed that Pb7–MT2­(II) has a greater acid tolerance and coordination stability than Pb7–MT2­(I), thereby retaining the Pb2+ coordination at acidic pH. The higher flexibility of Pb7–MT2­(II) renders it more accessible to lysosomal proteolysis than Pb7–MT2­(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.