Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter.
Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter.
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DOI：
10.1038/nature11542
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发表时间：
2012-11-22
期刊：
影响因子：
64.8
通讯作者：
Wang, Da-Neng
中科院分区：
文献类型：
--
作者：
Mancusso, Romina;Gregorio, G. Glenn;Liu, Qun;Wang, Da-Neng
在人体细胞中，胞质柠檬酸盐是合成脂肪酸、甘油三酯、胆固醇和低密度脂蛋白的主要前体。柠檬酸细胞质通过激活脂肪酸合成途径进一步调节细胞能量平衡，同时下调糖酵解和脂肪酸β-氧化途径（Supplementary Fig. 1）。肝脏和脂肪细胞是脂肪酸合成的两种主要组织类型，它们的脂肪酸合成速率与细胞质中柠檬酸盐的浓度直接相关。胞内柠檬酸盐浓度部分取决于通过Na+依赖的柠檬酸转运体（NaCT）穿过质膜的直接进口。同源果蝇基因的突变（INDY，我还没死）通过限制卡路里导致脂肪储存减少。最近，研究发现nact基因敲除小鼠的肝脏线粒体生物生成增加，脂质氧化和能量消耗增加，脂肪生成减少，这些因素共同保护小鼠免受肥胖和胰岛素抵抗。为了了解NaCT/INDY蛋白的转运机制，我们报道了细菌INDY同源物的3.2 Å晶体结构。每个蛋白结合一个柠檬酸盐分子和一个钠离子，它们的结合位点由保守的氨基酸基序定义，形成了理解转运蛋白特异性的结构基础。对两个对称转运体的结构进行比较表明，构象变化推动了底物易位。
In human cells, cytosolic citrate is a major precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the cell’s energy balance by activating the fatty acid synthesis pathway while down-regulating both the glycolysis and fatty acid β-oxidation pathways (Supplementary Fig. 1) . The rate of fatty acid synthesis in liver and adipose cells, the two major tissue types for such synthesis, correlates directly with the concentration of citrate in the cytosol . The cytosolic citrate concentration partially depends on direct import across the plasma membrane via the Na+-dependent citrate transporter (NaCT) . Mutations of the homologous fly gene (INDY, I’m Not Dead Yet) result in reduced fat storage through calorie restriction . More recently, NaCT-knockout mice have been found to have increased hepatic mitochondrial biogenesis, higher lipid oxidation and energy expenditure, and reduced lipogenesis, which taken together protect the mice from obesity and insulin resistance . To understand the transport mechanism of NaCT/INDY proteins, here we report the 3.2 Å crystal structure of a bacterial INDY homolog. One citrate molecule and one sodium ion are bound per protein, and their binding sites are defined by conserved amino acid motifs, forming the structural basis for understanding the transporters’ specificity. Comparison of the structures of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation.
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DOI：
10.1107/s090744491003982x
发表时间：
2011-04
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Evans PR
通讯作者：
Evans PR
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
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
5.6
作者：
Law, Christopher J.;Almqvist, Jonas;Wang, Da-Neng
通讯作者：
Wang, Da-Neng
影响因子：
2.9
作者：
Griffith, DA;Pajor, AM
通讯作者：
Pajor, AM