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首页> 外文期刊>Journal of Molecular Biology >Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein.
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Role of tryptophan residues in the recognition of mutagenic oxidized nucleotides by human antimutator MTH1 protein.

机译：色氨酸残基在人类抗突变剂MTH1蛋白识别诱变的氧化核苷酸中的作用。

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摘要

The human MTH1 antimutator protein hydrolyzes mutagenic oxidized nucleotides, and thus prevents their incorporation into DNA and any subsequent mutation. We have examined its great selectivity for oxidized nucleotides by analyzing the structure of the protein and its interaction with nucleotides, as reflected in the fluorescence of its tryptophan residues. The binding of nucleotides decreased the intensity of MTH1 protein fluorescence and red-shifted the emission peak, indicating that at least one tryptophan residue is close to the binding site. Oxidized nucleotides (2-OH-dATP and 8-oxo-dGTP) produced a larger decrease in fluorescence intensity than did unoxidized nucleotides, and MTH1 protein had a much higher binding affinity for oxidized nucleotides. Deconvolution of protein fluorescence by comparison of its quenching by positively (Cs(+)) and negatively (I(-)) charged ions indicated that the MTH1 tryptophan residues are in two different environments. One class of tryptophan residues is exposed to solvent but in a negatively charged environment; the other class is partially buried. While the binding of unoxidized nucleotides quenches the fluorescence of only class 1 tryptophan residue(s), the binding of oxidized nucleotides quenched that of class 2 tryptophan residue(s) as well. This suggests that selectivity is due to additional contact between the protein and the oxidized nucleotide. Mutation analysis indicated that the tryptophan residue at position 117, which is in a negative environment, is in contact with nucleotides. The negatively charged residues in the binding site probably correlate with the finding that nucleotide binding requires metal ions and depends upon their nature. Positively charged metal ions probably act by neutralizing the negatively charged nucleotide phosphate groups. (c) 2002 Elsevier Science Ltd.
机译：人类MTH1抗突变蛋白水解了诱变的氧化核苷酸，从而阻止了它们掺入DNA以及随后的任何突变。我们已经通过分析蛋白质的结构及其与核苷酸的相互作用，检查了其对氧化核苷酸的巨大选择性，这反映在其色氨酸残基的荧光上。核苷酸的结合降低了MTH1蛋白荧光的强度，并使发射峰红移，表明至少一个色氨酸残基靠近结合位点。氧化的核苷酸（2-OH-dATP和8-oxo-dGTP）与未氧化的核苷酸相比，荧光强度降低幅度更大，并且MTH1蛋白对氧化的核苷酸具有更高的结合亲和力。通过比较其带正电（Cs（+））和带负电（I（-））的猝灭，对蛋白质荧光进行解卷积表明，MTH1色氨酸残基位于两种不同的环境中。一类色氨酸残基暴露在溶剂中但处于带负电的环境中。另一类被部分掩埋。尽管未氧化的核苷酸的结合仅淬灭了1类色氨酸残基的荧光，但是氧化的核苷酸的结合也淬灭了2类色氨酸残基的荧光。这表明选择性是由于蛋白质与氧化核苷酸之间的额外接触所致。突变分析表明，处于负性环境的117位色氨酸残基与核苷酸接触。结合位点中带负电荷的残基可能与核苷酸结合需要金属离子并取决于其性质的发现有关。带正电的金属离子可能通过中和带负电的核苷酸磷酸基团而起作用。 （c）2002爱思唯尔科学有限公司。

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