The ups and downs of elevator-type di-/tricarboxylate membrane transporters.
The ups and downs of elevator-type di-/tricarboxylate membrane transporters.
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DOI：
10.1111/febs.16158
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发表时间：
2022-03
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影响因子：
--
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中科院分区：
文献类型：
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二价阴离子钠共转运体（DASS）家族包括钠驱动的阴离子共转运体和阴离子/阴离子交换体。该家族属于一个更广泛的离子转运蛋白超家族（ITS），它包括24个转运蛋白家族，包括AbgT抗生素外排转运蛋白家族。DASS家族中的人类蛋白具有重要的生理作用，是药物靶点。我们最近确定了人类钠依赖性柠檬酸转运体（NaCT）和嗜酸乳杆菌（LaINDY）的琥珀酸/二羧酸转运体的多个结构。这两种蛋白的结构与先前确定的VcINDY折叠具有高度的结构相似性。这些DASS蛋白结构与AbgT家族之间的保守性表明，VcINDY折叠代表了整个ITS超家族的整体蛋白质结构。NaCT和LaINDY的新结构分别是向内或向外的构象。这些结构中的结构域排列与底物跨膜转运的刚体升降机式运输机制一致。两个独立的NaCT结构与底物或抑制剂复合物使我们能够解释抑制机制，并提出了一种详细的分类方案，用于分组人类蛋白质中的致病突变。对DASS蛋白多种动力学状态的结构理解是详细描述其整个运输周期的第一步。肝细胞输入柠檬酸盐作为能量来源和脂肪酸合成的前体。这种摄取是通过质膜中钠离子驱动的柠檬酸转运体（NaCT）完成的。抑制摄取可以减少脂肪储存。我们测定了人类NaCT与抑制剂配合物的结构。该结构揭示了该化合物是如何抑制转运的，以及为什么它在人类中选择性地抑制NaCT而不是其他同源二羧酸转运蛋白。
The divalent anion sodium symporter (DASS) family contains both sodium-driven anion co-transporters and anion/anion exchangers. The family belongs to a broader Ion Transporter Superfamily (ITS), which comprises 24 families of transporters, including those of AbgT antibiotic efflux transporters. The human proteins in the DASS family play major physiological roles and are drug targets. We recently determined multiple structures of the human sodium-dependent citrate transporter (NaCT) and the succinate/dicarboxylate transporter from Lactobacillus acidophilus (LaINDY). Structures of both proteins show high degrees of structural similarity to the previously-determined VcINDY fold. Conservation between these DASS protein structures and those from the AbgT familiy indicates that the VcINDY fold represents the overall protein structure for the entire ITS superfamily. The new structures of NaCT and LaINDY are captured in the inward- or outward-facing conformations, respectively. The domain arrangements in these structures agree with a rigid-body elevator-type transport mechanism for substrate translocation across the membrane. Two separate NaCT structures in complex with a substrate or an inhibitor allowed us to explain the inhibition mechanism and propose a detailed classification scheme for grouping disease-causing mutations in the human protein. Structural understanding of multiple kinetic states of DASS proteins is a first step towards the detailed characterization of their entire transport cycle. Liver cells import citrate as an energy source and a precursor for fatty acid synthesis. This uptake is accomplished via the Na+-driven citrate transporter (NaCT) in the plasma membrane. Inhibition of uptake can reduce fat storage. We determined the structure of human NaCT in complex with an inhibitor. The structure reveals how the compound inhibits transport and why it inhibits NaCT selectively over other homologous dicarboxylate transporters in humans.
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DOI：
10.1152/ajpgi.00371.2006
发表时间：
2007-01-01
影响因子：
4.5
作者：
Gopal, Elangovan;Miyauchi, Seiji;Ganapathy, Vadivel
通讯作者：
Ganapathy, Vadivel
影响因子：
4.1
作者：
FANG, M;LOWENSTEIN, JM
通讯作者：
LOWENSTEIN, JM
影响因子：
5.6
作者：
Lolkema, JS;Slotboom, DJ
通讯作者：
Slotboom, DJ
影响因子：
4.1
作者：
Inoue, K;Fei, YJ;Ganapathy, V
通讯作者：
Ganapathy, V
影响因子：
4.8
作者：
Inoue, K;Zhuang, L;Ganapathy, V
通讯作者：
Ganapathy, V