pH-dependent coordination of Pb2+ to metallothionein2: structures and insight into lead detoxification.
pH-dependent coordination of Pb2+ to metallothionein2: structures and insight into lead detoxification.
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Pb2 与金属硫蛋白2 的 pH 依赖性配位：铅解毒的结构和见解
DOI：
10.1021/ic402452s
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发表时间：
2014-03-17
影响因子：
4.6
通讯作者：
Zhou F
中科院分区：
文献类型：
--
作者：
He Y;Liu M;Darabedian N;Liang Y;Wu D;Xiang J;Zhou F
铅是一种有毒的重金属，其在生物体内的解毒主要是通过与金属硫蛋白等金属蛋白的配位来实现的。Pb7-MT2(I)和Pb7-MT2(II)分别在中性和弱酸性条件下形成两种铅-MT络合物。然而，这两个络合物的结构对于更好地理解铅-MTS的解毒机理是至关重要的，目前还没有明确的解释。本工作采用紫外-可见光谱、圆二色谱和核磁共振相结合的方法，研究了不同pH条件下Pb2+与兔肝载脂蛋白-MT2及其两个单独结构域(载脂蛋白−α-MT2和载脂蛋白−β-MT2)的配位作用。结果表明，Pb7-MT2(I)中Pb2+的配位方式为三方锥PbS3，Pb7-Mt2(II)络合物中Pb2+的配位方式为混合三方锥PbS3、扭曲三方锥PbS2O1和扭曲四方锥PbS3O1。Pb7-MT2(II)中的O-给体配体被鉴定为天冬氨酸残基的2和56位的羧基。我们的研究还表明，Pb7-MT2(II)比Pb7-MT2(I)具有更强的耐酸性和配位稳定性，从而在酸性pH下保持了Pb2+的配位。Pb7-MT2(II)比Pb7-MT2(I)具有更高的柔韧性，使其更容易被溶酶体蛋白降解。在人apo-MT2与Pb2+的配位过程中也观察到了相似的光谱特征，这表明哺乳动物MT2在Pb2+配位化学上具有共性。揭示了两种不同的Pb7MT2−络合物的pH依赖性结构。研究了这两种络合物在蛋白质降解过程中的化学稳定性和结构柔性，以深入了解MTS对铅的解毒过程。兔肝Pb7−MT2(II)与人Pb7−MT2(II)具有相似的结构、化学和生物学特性，提示哺乳动物MT2与Pb2+的配位化学具有共性。
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. The pH-dependent structures of two different Pb7−MT2 complexes were revealed. The chemical stabilities and structural flexibility of these two complexes in proteolytic processing were investigated to gain insight into the lead detoxification process involving MTs. The similar structural, chemical, and biological properties between rabbit liver Pb7−MT2(II) and human Pb7−MT2(II) suggest a commonality in the Pb2+ coordination chemistry among mammalian MT2s.
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