Faculty of Biology Medicine and Health, The University of Manchester, UK.
Department of Chemistry, Johannes Gutenberg-University, Mainz, Germany.
FEBS Lett. 2020 Dec;594(23):3857-3875. doi: 10.1002/1873-3468.13921. Epub 2020 Sep 17.
The classic conceptualization of ATP binding cassette (ABC) transporter function is an ATP-dependent conformational change coupled to transport of a substrate across a biological membrane via the transmembrane domains (TMDs). The binding of two ATP molecules within the transporter's two nucleotide binding domains (NBDs) induces their dimerization. Despite retaining the ability to bind nucleotides, isolated NBDs frequently fail to dimerize. ABC proteins without a TMD, for example ABCE and ABCF, have NBDs tethered via elaborate linkers, further supporting that NBD dimerization does not readily occur for isolated NBDs. Intriguingly, even in full-length transporters, the NBD-dimerized, outward-facing state is not as frequently observed as might be expected. This leads to questions regarding what drives NBD interaction and the role of the TMDs or linkers. Understanding the NBD-nucleotide interaction and the subsequent NBD dimerization is thus pivotal for understanding ABC transporter activity in general. Here, we hope to provide new insights into ABC protein function by discussing the perplexing issue of (missing) NBD dimerization in isolation and in the context of full-length ABC proteins.
经典的 ATP 结合盒（ABC）转运蛋白功能概念是一种 ATP 依赖性构象变化，与通过跨膜域（TMD）跨生物膜转运底物相关联。转运蛋白的两个核苷酸结合域（NBD）内的两个 ATP 分子的结合诱导它们的二聚化。尽管保留了结合核苷酸的能力，但分离的 NBD 通常不能二聚化。例如 ABCE 和 ABCF 没有 TMD 的 ABC 蛋白，其 NBD 通过精细的接头连接，进一步支持分离的 NBD 不易发生 NBD 二聚化。有趣的是，即使在全长转运蛋白中，NBD-二聚化的外向构象也不像预期的那样频繁出现。这引发了关于什么驱动 NBD 相互作用以及 TMD 或接头的作用的问题。因此，了解 NBD-核苷酸相互作用以及随后的 NBD 二聚化对于理解 ABC 转运蛋白的一般活性至关重要。在这里，我们希望通过讨论全长 ABC 蛋白中分离和整体环境下（缺失）NBD 二聚化的复杂问题，为 ABC 蛋白功能提供新的见解。
