Mechanism of substrate binding and transport in BASS transporters.
Mechanism of substrate binding and transport in BASS transporters.
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DOI：
10.7554/elife.89167
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发表时间：
2023-11-14
期刊：
影响因子：
7.7
通讯作者：
Cameron AD
中科院分区：
文献类型：
--
作者：
Becker P;Naughton F;Brotherton D;Pacheco-Gomez R;Beckstein O;Cameron AD
胆汁酸钠转运体(BASS)家族可跨膜转运多种分子，包括人体的胆汁酸和植物中的小代谢物。这些转运蛋白，其中许多是钠偶联的，已经被证明使用一种提升的运输机制，但到底底物结合是如何耦合到钠离子结合和运输的还不清楚。在这里，我们求解了脑膜炎奈瑟氏菌转运蛋白(ASBTNM)与泛酸的络合物的晶体结构，泛酸是ASBTNM的潜在底物。贝斯家族的特征是两个螺旋在蛋白质的中心交叉，由两个钠离子错综复杂地结合在一起。我们观察到，特别是在这个交叉区域中，Pantoate结合在两个相对螺旋的N端之间。在分子动力学模拟中，当有钠离子存在时，泛酸盐保持在这个位置，但在没有钠离子时，泛酸盐的流动性更强。比较存在和不存在泛酸的结构表明，泛酸引起了其中一个交叉螺旋的构象变化。这修改了两个域之间的界面，这两个域相对于彼此移动以引发电梯机制。这些结果不仅对ASBTNM有影响，而且对整个贝斯家族，甚至对通过电梯机制工作的其他运输器也有影响。
The bile acid sodium symporter (BASS) family transports a wide array of molecules across membranes, including bile acids in humans, and small metabolites in plants. These transporters, many of which are sodium-coupled, have been shown to use an elevator mechanism of transport, but exactly how substrate binding is coupled to sodium ion binding and transport is not clear. Here, we solve the crystal structure at 2.3 Å of a transporter from Neisseria meningitidis (ASBTNM) in complex with pantoate, a potential substrate of ASBTNM. The BASS family is characterised by two helices that cross-over in the centre of the protein in an arrangement that is intricately held together by two sodium ions. We observe that the pantoate binds, specifically, between the N-termini of two of the opposing helices in this cross-over region. During molecular dynamics simulations the pantoate remains in this position when sodium ions are present but is more mobile in their absence. Comparison of structures in the presence and absence of pantoate demonstrates that pantoate elicits a conformational change in one of the cross-over helices. This modifies the interface between the two domains that move relative to one another to elicit the elevator mechanism. These results have implications, not only for ASBTNM but for the BASS family as a whole and indeed other transporters that work through the elevator mechanism.
影响因子：
11.4
作者：
Hatton, Caitlin E.;Brotherton, Deborah H.;Spencer, Mahalah;Cameron, Alexander D.
通讯作者：
Cameron, Alexander D.