Université Paris-Sud, Institut de Génétique et Microbiologie, UMR CNRS 8621, Bâtiment 409, 91405 Orsay Cedex, France.
Essays Biochem. 2011 Sep 7;50(1):1-17. doi: 10.1042/bse0500001.
This chapter concentrates mainly on structural and mechanistic aspects of ABC (ATP-binding cassette) transporters and, as an example of the physiological significance of these proteins, on lipid transport, vitally important for human health. The chapter considers those aspects of ABC transporter function that appear reasonably well established, those that remain controversial and what appear to be emerging themes. Although we have seen dramatic progress in ABC protein studies in the last 20 years, we are still far from a detailed molecular understanding of function. Nevertheless two critical steps - capture and release of allocrites (transport substrates) involving a binding cavity in the membrane domain, and hydrolysis of ATP by the NBD (nucleotide-binding domain) dimer - are now described by persuasive and testable models: alternating access, and sequential firing of catalysis sites respectively. However, these need to be tested rigorously by more structural and biochemical studies. Other aspects considered include the level at which ATP binding and dimer activation are controlled, the nature of the power stroke delivering mechanical energy for transport, and some unexpected and intriguing differences between importers and exporters. The chapter also emphasizes that some ABC transporters, although important for elimination of toxic compounds (xenobiotics), are also increasingly seen to play crucial roles in homoeostatic regulation of membrane biogenesis and function through translocation of endogenous allocrites such as cholesterol. Another emerging theme is the identification of accessory domains and partners for ABC proteins, resulting in a corresponding widening of the range of activities. Finally, what are the prospects for translational research and ABC transporters?
这一章主要集中在 ABC（ATP 结合盒）转运蛋白的结构和机制方面，并以这些蛋白质在脂质转运方面的生理意义为例，脂质转运对人类健康至关重要。本章考虑了 ABC 转运蛋白功能中那些似乎已经得到合理确立的方面、那些仍然存在争议的方面以及那些似乎正在出现的主题。尽管在过去的 20 年中，我们在 ABC 蛋白研究方面取得了巨大进展，但我们仍然远未从详细的分子水平理解其功能。尽管如此，两个关键步骤——涉及膜域结合腔的外来配体（转运底物）的捕获和释放，以及 NBD（核苷酸结合域）二聚体的 ATP 水解——现在都由有说服力和可测试的模型来描述：交替访问和催化位点的顺序激发。然而，这些需要通过更多的结构和生化研究来严格检验。其他方面还包括 ATP 结合和二聚体激活的控制水平、为转运提供机械能量的力臂的性质，以及在输入蛋白和输出蛋白之间存在一些意想不到和有趣的差异。这一章还强调，尽管一些 ABC 转运蛋白对于消除有毒化合物（外源性物质）非常重要，但它们也越来越被认为通过转运内源性外来配体（如胆固醇）在膜生物发生和功能的同型调节中发挥关键作用。另一个正在出现的主题是鉴定 ABC 蛋白的辅助结构域和伴侣，从而相应地拓宽了其活性范围。最后，转化研究和 ABC 转运蛋白的前景如何？
