来自美国纽约大学医学院的科学家报告了对依赖于Na+的一个细菌柠檬酸运输因子的X-射线晶体结构及运输活性所做的研究。这些结构和生化研究揭示了特定构形变化是怎样促进穿过细胞膜的机制转位的。

-2012年11月22日《自然》

中文翻译


【题目】细菌钠依赖的二羧酸运载体的结构和机制

【译文】人细胞中,细胞质中柠檬酸盐是脂肪酸、甘油三酯、胆固醇及低密度脂蛋白合成的主要前体。胞质柠檬酸盐通过激活脂肪酸合成通路而下调糖酵解和脂肪酸β氧化通路进一步调控细胞能量平衡。肝细胞和脂肪细胞(合成的两种主要组织类型)中脂肪酸合成率直接与胞质溶胶中柠檬酸盐的浓度相关,胞质柠檬酸浓度部分取决于通过Na+依赖的柠檬酸盐运载体(NaCT)穿过细胞膜的直接输入。同源fly基因的突变通过柠檬酸盐限制导致脂肪存储减少。近期,有研究发现Nact (又称Slc13a5)敲除的小鼠增加了肝脏线粒体生物发生,更高的脂质氧化和能量消耗,而脂肪生成减少,这些联合起来防止小鼠产生肥胖症和胰岛素耐受。为了理解NaCT和INDY蛋白的运输机制,本研究报道了细菌性INDY同源物的分辨率为3.2 Å的晶体结构。每个蛋白结合一个柠檬酸盐分子和一个钠离子,它们的结合位点可通过保守的氨基酸基序来定义,这形成了理解运载体特异性的结构基础。比对运载体两个对称部分的结构表明了促进底物易位的构象变化。

英文原稿


[Title]: Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter

[Authors]:Romina Mancusso,1, 2 G. Glenn Gregorio,1 Qun Liu3 & Da-Neng Wang1, 4

[Abstract]In human cells, cytosolic citrate is a chief precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the energy balance of the cell by activating the fatty-acid-synthesis pathway while downregulating both the glycolysis and fatty-acid β-oxidation pathways. The rate of fatty-acid synthesis in liver and adipose cells, the two main tissue types for such synthesis, correlates directly with the concentration of citrate in the cytosol, with the cytosolic citrate concentration partially depending on direct import across the plasma membrane through 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 (also known as Slc13a5)-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 and INDY proteins, here we report the 3.2 Å crystal structure of a bacterial INDY homologue. 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 specificity of the transporter. Comparison of the structures of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation.

原文地址

http://www.nature.com/nature/journal/v491/n7425/full/nature11542.html

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