Organic anion transporting polypeptides of the OATP/SLCO superfamily:: Identification of new members in nonmammalian species, comparative modeling and a potential transport mode
Organic anion transporting polypeptides of the OATP/SLCO superfamily:: Identification of new members in nonmammalian species, comparative modeling and a potential transport mode
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DOI：
10.1007/s00232-005-7004-x
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发表时间：
2005-01-01
影响因子：
2.4
通讯作者：
Mizuguchi, K
中科院分区：
文献类型：
--
作者：
Meier-Abt, F;Mokrab, Y;Mizuguchi, K
有机阴离子转运多肽（人，OATP;其他动物，Oatps;基因符号，SLCO/Slco）形成一个转运蛋白超家族，介导两亲性底物跨动物细胞质膜的转运。到目前为止，已在人类、大鼠和小鼠组织中发现了OATP/Oatps。在这项研究中，我们使用生物信息学的工具来检测新成员的OATP/SLCO超家族在非哺乳动物物种，并建立模型的三维结构的OATP/Oatps。新的OATP/SLCO超家族成员，其中一些形成不同的新家族，在鸡，斑马鱼，青蛙，果蝇和蠕虫物种中被鉴定。在植物、酵母和细菌中缺乏OATP/SLCO超家族成员，这表明在动物王国的早期祖先中出现了古老的Oatp蛋白。基于转运蛋白主要易化剂超家族的已知结构，生成了代表性成员OATP 1B 3和OATP 2B 1的结构模型。一个模型也建立了跨膜螺旋9和10之间的大细胞外区域，确定一个新的同源性与Kazal型丝氨酸蛋白酶抑制剂。沿着静电势和关键氨基酸残基的保守性，我们提出了所有OATP/OATP的共同转运机制，即底物通过中心带正电荷的孔以摇杆开关类型的机制转运。几个氨基酸残基被确定，可能发挥关键作用，在拟议的运输机制。
Organic anion-transporting polypeptides (human, OATPs; other animals, Oatps; gene symbol, SLCO/Slco) form a transport protein superfamily that mediates the translocation of amphipathic substrates across the plasma membrane of animal cells. So far, OATPs/Oatps have been identified in human, rat and mouse tissues. In this study, we used bioinformatic tools to detect new members of the OATP/SLCO superfamily in nonmammalian species and to build models for the three-dimensional structure of OATPs/Oatps. New OATP/SLCO superfamily members, some of which form distinct novel families, were identified in chicken, zebrafish, frog, fruit fly and worm species. The lack of OATP/SLCO superfamily members in plants, yeast and bacteria suggests the emergence of an ancient Oatp protein in an early ancestor of the animal kingdom. Structural models were generated for the representative members OATP1B3 and OATP2B1 based on the known structures of the major facilitator superfamily of transport proteins. A model was also built for the large extracellular region between transmembrane helices 9 and 10, following the identification of a novel homology with the Kazal-type serine protease inhibitors. Along with the electrostatic potential and the conservation of key amino acid residues, we propose a common transport mechanism for all OATPs/Oatps, whereby substrates are translocated through a central, positively charged pore in a rocker-switch type of mechanism. Several amino acid residues were identified that may play crucial roles in the proposed transport mechanism.