• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Nature >Structural basis of the alternating-access mechanism in a bile acid transporter
【24h】

Structural basis of the alternating-access mechanism in a bile acid transporter

机译：胆汁酸转运蛋白中交替进入机制的结构基础

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Bile acids are synthesized from cholesterol in hepatocytes and secreted through the biliary tract into the small intestine, where they aid in absorption of lipids and fat-soluble vitamins. Through a process known as enterohepatic recirculation, more than 90% of secreted bile acids are then retrieved from the intestine and returned to the liver for resecretion. In humans, there are two Na~+-dependent bile acid transporters involved in enterohepatic recirculation, the Na~+-taurocholate co-transporting polypeptide (NTCP; also known as SLC10A1) expressed in hepatocytes, and the apical sodium-dependent bile acid transporter (ASBT; also known as SLC10A2) expressed on enterocytes in the terminal ileum. In recent years, ASBT has attracted much interest as a potential drug target for treatment of hyper-cholesterolaemia, because inhibition of ASBT reduces reabsorption of bile acids, thus increasing bile acid synthesis and consequently cholesterol consumption. However, a lack of three-dimensional structures of bile acid transporters hampers our ability to understand the molecular mechanisms of substrate selectivity and transport, and to interpret the wealth of existing functional data. The crystal structure of an ASBT homologue from Neisseria meningiti-dis (ASBT_(NM)) in detergent was reported recently, showing the protein in an inward-open conformation bound to two Na~+ and a taurocholic acid. However, the structural changes that bring bile acid and Na~+ across the membrane are difficult to infer from a single structure. To understand the structural changes associated with the coupled transport of Na~+ and bile acids, here we solved two structures of an ASBT homologue from Yersinia frederiksenii (ASBTyf) in a lipid environment, which reveal that a large rigid-body rotation of a substrate-binding domain gives the conserved 'crossover' region, where two discontinuous helices cross each other, alternating accessibility from either side of the cell membrane. This result has implications for the location and orientation of the bile acid during transport, as well as for the translocation pathway for Na~+.
机译：胆汁酸是由肝细胞中的胆固醇合成的，并通过胆道分泌到小肠中，在那里它们有助于吸收脂质和脂溶性维生素。通过称为肠肝循环的过程，从肠中回收了90％以上的分泌胆汁酸，然后返回肝脏进行分泌。在人类中，有两种Na +依赖胆汁酸转运蛋白参与肠肝循环，肝细胞中表达的Na〜-牛磺胆酸盐共转运多肽（NTCP；也称为SLC10A1）和顶端钠依赖性胆酸转运蛋白（ASBT；也称为SLC10A2）在回肠末端的肠上皮细胞中表达。近年来，ASBT作为治疗高胆固醇血症的潜在药物靶标引起了广泛兴趣，因为抑制ASBT会降低胆汁酸的重吸收，从而增加胆汁酸的合成并因此增加胆固醇的消耗。但是，缺乏胆汁酸转运蛋白的三维结构会妨碍我们了解底物选择性和转运的分子机制以及解释大量现有功能数据的能力。最近报道了洗涤剂中脑膜炎奈瑟氏球菌（ASBT_（NM））的ASBT同源物的晶体结构，显示该蛋白呈与两个Na +和牛磺胆酸结合的向内构象。然而，难以从单个结构推断出使胆汁酸和Na +穿过膜的结构变化。为了了解与Na〜+和胆汁酸耦合运输相关的结构变化，我们在脂质环境中解析了耶尔森氏菌（Yersinia frederiksenii）（ASBTyf）的ASBT同源物的两个结构，这揭示了底物的大刚体旋转结合结构域给出了一个保守的“交叉”区域，其中两个不连续的螺旋相互交叉，从细胞膜的任一侧交替进入。这一结果对胆汁酸在运输过程中的位置和取向以及Na〜+的易位途径有影响。

著录项

  • 来源
    《Nature》 |2014年第7484期|569-573|共5页
  • 作者

    Xiaoming Zhou; Elena J. Levin; Yaping Pan; Jason G. McCoy; Ruchika Sharma; Brian Kloss; Renato Bruni; Matthias Quick; Ming Zhou;

  • 作者单位

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA,Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA;

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA;

    Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA;

    New York Consortium on Membrane Protein Structure, New York, New York 10027, USA;

    New York Consortium on Membrane Protein Structure, New York, New York 10027, USA;

    Department of Psychiatry and Center for Molecular Recognition, Columbia University, New York, New York 10032, USA,New York State Psychiatric Institute, Division of Molecular Therapeutics, New York, New York 10032, USA;

    Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA,Department of Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA,lon Channel Research and Drug Development Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号