Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
MTA-SE Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
Adv Cancer Res. 2015;125:97-137. doi: 10.1016/bs.acr.2014.10.004. Epub 2015 Jan 8.
This chapter deals with the interactions of two medically important multidrug ABC transporters (MDR-ABC), ABCB1 and ABCG2, with lipid molecules. Both ABCB1 and ABCG2 are capable of transporting a wide range of hydrophobic drugs and xenobiotics and are involved in cancer chemotherapy resistance. Therefore, the exploration of their mechanism of action has major therapeutic consequences. As discussed here in detail, both ABCB1 and ABCG2 are significantly affected by various lipid compounds especially those residing in their close proximity in the plasma membrane. ABCB1 is capable of transporting lipids and lipid derivatives, and thus may alter the general membrane composition by "flopping" membrane lipid constituents, while there is no such information regarding ABCG2. Still, both ABCB1 and ABCG2 show complex interactions with a variety of lipid molecules, and the transporters are significantly modulated by cholesterol and cholesterol derivatives at the posttranslational level. In this chapter, we explore the molecular details of the direct transporter-lipid interactions, the potential role of lipid-sensor domains within the proteins, as well as the application of experimental site-directed mutagenesis, detailed structural studies, and in silico modeling for examining these interactions. We also discuss the regulation of ABCB1 and ABCG2 expression at the transcriptional level, occurring through nuclear receptors involved in lipid sensing. The better understanding of lipid interactions with these medically important MDR-ABC transporters may significantly improve further drug development and clinical treatment options.
本章涉及两种医学上重要的多药 ABC 转运蛋白（MDR-ABC），ABCB1 和 ABCG2，与脂质分子的相互作用。ABCB1 和 ABCG2 均能够转运广泛的疏水性药物和外源性物质，并且与癌症化疗耐药性有关。因此，探索它们的作用机制具有重要的治疗意义。如这里详细讨论的那样，多种脂质化合物，特别是那些位于质膜附近的脂质化合物，显著影响 ABBC1 和 ABCG2。ABCB1 能够转运脂质和脂质衍生物，因此可能通过“翻转”膜脂质成分来改变总体膜组成，而关于 ABCG2 则没有这样的信息。尽管如此，ABCB1 和 ABCG2 均与多种脂质分子表现出复杂的相互作用，并且胆固醇和胆固醇衍生物在翻译后水平上显著调节转运蛋白。在本章中，我们探讨了直接转运蛋白-脂质相互作用的分子细节、蛋白质内脂质传感器结构域的潜在作用，以及应用实验性定点突变、详细的结构研究和计算机模拟来研究这些相互作用。我们还讨论了通过参与脂质感应的核受体在转录水平上调节 ABCB1 和 ABCG2 的表达。更好地理解这些医学上重要的 MDR-ABC 转运蛋白与脂质的相互作用可能会显著改善进一步的药物开发和临床治疗选择。
