Asymmetry of inverted-topology repeats in the AE1 anion exchanger suggests an elevator-like mechanism.
Asymmetry of inverted-topology repeats in the AE1 anion exchanger suggests an elevator-like mechanism.
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DOI：
10.1085/jgp.201711836
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发表时间：
2017-12-04
期刊：
影响因子：
--
通讯作者：
Forrest LR
中科院分区：
文献类型：
--
作者：
Ficici E;Faraldo-Gómez JD;Jennings ML;Forrest LR
阴离子交换剂1通过尚不清楚的机制催化氯离子和碳酸氢根离子的跨膜反向转运。通过模拟其面向内的状态并将其与已知的面向外的形式进行比较，Ficici等人假设这种转运蛋白具有类似电梯的机制。膜转运阴离子交换器1（AE 1）或带3是血液中二氧化碳转运和肾集合管中尿液酸化过程中的关键组分。在红细胞和集合管α-插入细胞的基底外侧膜中，AE 1的作用是催化氯离子与碳酸氢根的一对一交换。经过几十年的生物化学和功能研究，AE 1跨膜区的结构，催化阴离子交换反应，终于被确定。AE 1二聚体的每个原聚体包含两个具有反向跨膜拓扑结构的重复序列，但这些重复序列的结构不同。这种不对称性导致推定的底物结合位点仅暴露于细胞外空间，这与阴离子交换通过交替进入机制发生的预期一致。在这里，我们假设，未知的，面向内的构象结果从反转这种不对称性，我们提出了一个模型，这种状态构建使用重复交换同源建模。通过比较这个面向内的模型与面向外的实验结构，我们预测，AE 1的机制涉及的基板结合域相对于近静止的二聚化域和膜平面的电梯样运动。这一假设是在定性协议与广泛的生化和功能的数据，我们详细审查，并提出了新的途径的实验。
Anion exchanger 1 catalyzes the transmembrane antiport of chloride and bicarbonate ions through a mechanism that has remained unclear. By modeling its inward-facing state and comparing it with the known outward-facing form, Ficici et al. hypothesize that this transporter features an elevator-like mechanism. The membrane transporter anion exchanger 1 (AE1), or band 3, is a key component in the processes of carbon-dioxide transport in the blood and urinary acidification in the renal collecting duct. In both erythrocytes and the basolateral membrane of the collecting-duct α-intercalated cells, the role of AE1 is to catalyze a one-for-one exchange of chloride for bicarbonate. After decades of biochemical and functional studies, the structure of the transmembrane region of AE1, which catalyzes the anion-exchange reaction, has finally been determined. Each protomer of the AE1 dimer comprises two repeats with inverted transmembrane topologies, but the structures of these repeats differ. This asymmetry causes the putative substrate-binding site to be exposed only to the extracellular space, consistent with the expectation that anion exchange occurs via an alternating-access mechanism. Here, we hypothesize that the unknown, inward-facing conformation results from inversion of this asymmetry, and we propose a model of this state constructed using repeat-swap homology modeling. By comparing this inward-facing model with the outward-facing experimental structure, we predict that the mechanism of AE1 involves an elevator-like motion of the substrate-binding domain relative to the nearly stationary dimerization domain and to the membrane plane. This hypothesis is in qualitative agreement with a wide range of biochemical and functional data, which we review in detail, and suggests new avenues of experimentation.
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人红细胞转运蛋白中细胞外赖氨酸残基的功能。
影响因子：
3.8
作者：
Jennings, M L;Monaghan, R;Douglas, S M;Nicknish, J S
通讯作者：
Nicknish, J S
DOI：
10.1085/jgp.109.3.345
发表时间：
1997-03
期刊：
The Journal of general physiology
影响因子：
--
作者：
Chernova MN;Jiang L;Crest M;Hand M;Vandorpe DH;Strange K;Alper SL
通讯作者：
Alper SL
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：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M