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首页> 外文期刊>Biochemistry >Functional impact of a single mutation within the transmembrane domain of the multidrug ABC transporter Pdr5
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Functional impact of a single mutation within the transmembrane domain of the multidrug ABC transporter Pdr5

机译：多药ABC转运蛋白Pdr5跨膜域内单个突变的功能影响

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摘要

The pleiotropic drug resistance network in budding yeast presents a first line of defense against xenobiotics, which is formed by primary and secondary active membrane transporters. Among these transporters, the ABC transporter Pdr5 is a key component, because it confers resistance against a broad spectrum of such cytotoxic agents. Furthermore, it represents a model system for homologous transporters from pathogenic fungi and has been intensively studied in the past. In addition to other mutational studies, the S1360F mutation of Pdr5 was found to modulate substrate specificity and resistance. Notably, in the S1360F background, the resistance against the immunosuppressant FK506 is drastically increased. We present a detailed analysis of this mutation that is located in the predicted cytosolic part of transmembrane helix 11. Our data demonstrate that kinetic and thermodynamic parameters of the S1360F mutant are similar to those of the wild-type protein, except for FK506-inhibited ATPase activity and the degree of competitive inhibition. In summary, our results indicate that the S1360F mutation within the transmembrane domain interferes drastically with the ability of the nucleotide-binding domains to hydrolyze ATP by interfering with interdomain crosstalk.
机译：发芽酵母中的多效药物耐药性网络提供了针对异种生物的第一道防线，这是由一级和二级活性膜转运蛋白形成的。在这些转运蛋白中，ABC转运蛋白Pdr5是关键成分，因为它赋予了对多种此类细胞毒剂的抗性。此外，它代表了来自病原真菌的同源转运蛋白的模型系统，并且在过去已经进行了深入研究。除了其他突变研究之外，还发现Pdr5的S1360F突变可调节底物特异性和耐药性。值得注意的是，在S1360F背景下，对免疫抑制剂FK506的抵抗力急剧增加。我们提供了对该突变的详细分析，该突变位于跨膜螺旋11的预计胞质部分。我们的数据表明，S1360F突变体的动力学和热力学参数与野生型蛋白相似，但FK506抑制的ATPase除外。活性和竞争抑制的程度。总而言之，我们的结果表明跨膜结构域内的S1360F突变通过干扰域间串扰而严重干扰核苷酸结合域水解ATP的能力。

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