Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing
Functional diversification of sea urchin ABCC1 (MRP1) by alternative splicing
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DOI：
10.1152/ajpcell.00029.2016
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发表时间：
2016-06-01
影响因子：
5.5
通讯作者：
Hamdoun, Amro
中科院分区：
文献类型：
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作者：
Gokirmak, Tufan;Campanale, Joseph P.;Hamdoun, Amro
多药耐药蛋白（MRP）家族编码多种atp结合盒（ABC）转运蛋白，在发育、疾病和体内平衡中发挥多种作用。理解MRP的演变是揭示它们在这些不同过程中的作用的核心。海胆在了解脊椎动物蛋白质的进化中占有重要的系统发育地位，是研究ABC转运体的重要无脊椎动物模型系统。我们使用系统发育分析来研究MRP转运体的进化和功能方法，以确定海胆MRP1（也称为SpABCC1）的功能形式。SpABCC1是海胆中唯一的MRP同源物，与人类MRP1、MRP3和MRP6 （ABCC1、ABCC3和ABCC6）转运蛋白同源。然而，外排分析显示，对底物相互作用至关重要的外显子22的选择性剪接可能使海胆MRP1的功能多样化。系统发育比较还表明，虽然MRP1、MRP3和MRP6转运体可能来自基础后口动物的单一转运体，但在无脊椎动物中，选择性剪接似乎是功能多样化的主要模式，而复制可能在脊椎动物中起着更重要的作用。这些结果为MRP转运体的进化起源以及在不同动物群体中使其功能多样化的潜在机制提供了更深入的了解。
The multidrug resistance protein (MRP) family encodes a diverse repertoire of ATP-binding cassette (ABC) transporters with multiple roles in development, disease, and homeostasis. Understanding MRP evolution is central to unraveling their roles in these diverse processes. Sea urchins occupy an important phylogenetic position for understanding the evolution of vertebrate proteins and have been an important invertebrate model system for study of ABC transporters. We used phylogenetic analyses to examine the evolution of MRP transporters and functional approaches to identify functional forms of sea urchin MRP1 (also known as SpABCC1). SpABCC1, the only MRP homolog in sea urchins, is co-orthologous to human MRP1, MRP3, and MRP6 (ABCC1, ABCC3, and ABCC6) transporters. However, efflux assays revealed that alternative splicing of exon 22, a region critical for substrate interactions, could diversify functions of sea urchin MRP1. Phylogenetic comparisons also indicate that while MRP1, MRP3, and MRP6 transporters potentially arose from a single transporter in basal deuterostomes, alternative splicing appears to have been the major mode of functional diversification in invertebrates, while duplication may have served a more important role in vertebrates. These results provide a deeper understanding of the evolutionary origins of MRP transporters and the potential mechanisms used to diversify their functions in different groups of animals.