Institute of Biochemistry, Biocenter, Goethe University Frankfurt, Frankfurt, Germany.
Nat Chem Biol. 2010 Aug;6(8):572-80. doi: 10.1038/nchembio.410.
How ABC transporters work is a key issue because of their important roles in multidrug resistance of pathogenic bacteria, reduced efficacy of antitumor drugs, cholesterol metabolism, cell homeostasis and immune response. In the past few years, significant progress has been made in crystallization and structure determination of (mostly) bacterial ABC transporters, as well as in functional studies on ABC systems involved in human pathology. In this review, we use the transporter associated with antigen processing (TAP) to illustrate what is known regarding the mechanism of substrate transport. We also discuss the chemical basis of substrate recognition by TAP and the allosteric cross-talk between the binding of substrate, the release of chemical energy by ATP hydrolysis and cross-membrane translocation. Finally, we detail the role of TAP in a large macromolecular assembly, which optimally loads MHC class I molecules, and the interference with this machinery by TAP-targeted viral factors. Because of structural and probable mechanistic similarities, the understanding of the detailed structure and mechanism of TAP will be applicable to all ABC systems, including those of medical relevance.
ABC 转运蛋白的工作机制是一个关键问题，因为它们在致病菌的多药耐药性、抗肿瘤药物疗效降低、胆固醇代谢、细胞内稳态和免疫反应中起着重要作用。在过去的几年中，在（主要是）细菌 ABC 转运蛋白的结晶和结构确定方面，以及在涉及人类病理学的 ABC 系统的功能研究方面都取得了重大进展。在这篇综述中，我们使用与抗原加工相关的转运蛋白（TAP）来说明已知的底物转运机制。我们还讨论了 TAP 对底物的识别的化学基础，以及底物结合、ATP 水解释放化学能和跨膜转运之间的变构串扰。最后，我们详细介绍了 TAP 在一个大型大分子组装体中的作用，该组装体最佳地加载 MHC Ⅰ类分子，以及 TAP 靶向的病毒因子对该机制的干扰。由于结构和可能的机制相似性，对 TAP 的详细结构和机制的理解将适用于所有 ABC 系统，包括具有医学相关性的系统。
