Structural models of the NaPi-II sodium-phosphate cotransporters.
Structural models of the NaPi-II sodium-phosphate cotransporters.
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DOI：
10.1007/s00424-018-2197-x
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发表时间：
2019-01
期刊：
影响因子：
--
通讯作者：
Forrest LR
中科院分区：
文献类型：
--
作者：
Fenollar-Ferrer C;Forrest LR
由于缺乏有关NaPi-II磷酸钠转运蛋白的结构信息，长期以来，通过钠依赖性跨膜吸收了解磷酸盐稳态的分子机制的进展一直受到阻碍。对于许多其他耦合转运蛋白，即使是那些无关的NaPi-II，内部重复的元素已被揭示为一个关键的功能，是固有的。在这里，我们回顾最近的结构预测研究NaPi-II转运蛋白。试图确定NaPi-II转运蛋白的结构模板已经利用结构重复的角度来揭示与二羧酸钠共转运蛋白（DASS）的关系。这一启示允许预测的三维结构模型的人类NaPi-IIa和比目鱼NaPi-IIb，其折叠进行了评估，通过比较现有的生化数据概述了跨膜拓扑结构和溶剂的可及性的蛋白质的各个区域。使用这些结构模型，结合位点的钠和磷酸盐提出。预测的网站进行了测试和细化的基础上详细的电生理和生物化学研究，并通过比较与随后报道的结构属于AbgT家族的转运蛋白进行验证。与DASS转运蛋白VcINDY的比较表明，构象机制涉及一个大的，两个结构域的结构变化，称为电梯样机制。这些结构模型为进一步研究钠-磷酸盐转运的底物结合、构象变化、动力学和能量学提供了基础。我们讨论了未来的机遇，以及仍然存在的挑战。
Progress towards understanding the molecular mechanisms of phosphate homeostasis through sodium-dependent transmembrane uptake has long been stymied by the absence of structural information about the NaPi-II sodium-phosphate transporters. For many other coupled transporters, even those unrelated to NaPi-II, internal repeated elements have been revealed as a key feature that is inherent to their function. Here, we review recent structure prediction studies for NaPi-II transporters. Attempts to identify structural templates for NaPi-II transporters have leveraged the structural repeat perspective to uncover an otherwise obscured relationship with the dicarboxylate-sodium symporters (DASS). This revelation allowed the prediction of three-dimensional structural models of human NaPi-IIa and flounder NaPi-IIb, whose folds were evaluated by comparison with available biochemical data outlining the transmembrane topology and solvent accessibility of various regions of the protein. Using these structural models, binding sites for sodium and phosphate were proposed. The predicted sites were tested and refined based on detailed electrophysiological and biochemical studies and were validated by comparison with subsequently reported structures of transporters belonging to the AbgT family. Comparison with the DASS transporter VcINDY suggested a conformational mechanism involving a large, two-domain structural change, known as an elevator-like mechanism. These structural models provide a foundation for further studies into substrate binding, conformational change, kinetics, and energetics of sodium-phosphate transport. We discuss future opportunities, as well as the challenges that remain.
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DOI：
10.1073/pnas.0505882102
发表时间：
2005-08-30
影响因子：
11.1
作者：
Bacconi, A;Virkki, LV;Forster, IC
通讯作者：
Forster, IC
影响因子：
5.5
作者：
Ghezzi, Chiara;Murer, Heini;Forster, Ian C.
通讯作者：
Forster, Ian C.
DOI：
10.1073/pnas.0804659105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Forrest, Lucy R.;Zhang, Yuan-Wei;Rudnick, Gary
通讯作者：
Rudnick, Gary
影响因子：
3.4
作者：
Patti, Monica;Fenollar-Ferrer, Cristina;Forster, Ian C.
通讯作者：
Forster, Ian C.
影响因子：
5.8
作者：
Olivella, Mireia;Gonzalez, Angel;Deupi, Xavier
通讯作者：
Deupi, Xavier