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Identification and functional characterization of all the genes of heterodimeric amino acid transporter family by means of whole genome information

利用全基因组信息对异二聚体氨基酸转运蛋白家族所有基因进行鉴定和功能表征

基本信息

批准号：
14570085
负责人：
KANAI Yoshikatsu
金额：
$ 2.62万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570085/
关键词：
Amino acid transporter membrane transport genome postgenome SLC Heterodimeric protein epithelial transport

项目摘要

Heterodimeric amino acid transporters are formed by disulfide bonding of a twelve-membrane spanning protein (catalytic subunit) and a single membrane spanning protein (regulatory subunit). We have performed BLAST searches of human and mouse genome data bases using amino acid sequences of LAT1, BAT1 and CAT1 as queries. We have found 5 new genes, SLC7-N1〜5, as new members of SLC7 family. By searching EST (expressed sequence tag) data bases, we have concluded that two of them (SLC7-N4 and SLC7-N5) are pseudogenes, because they never appear in EST data bases. SLC7-N1 possesses 12 transmembrane domains and is supposed to be a catalytic subunit of heterodimeric amino acid transporters. We have named it AGT-1. AGT-1 protein is found on the basolateral membrane of proximal and distal tubules of mouse kidney. Because AGT-1 is supposed to be linked with unknown regulatory subunit, we have generated fusion proteins in which AGT-1 is connected with known regulatory subunits 4F2hc or rBAT and expressed them in Xenopus oocytes. The fusion proteins appear on the plasma membrane and exhibit the transport of acidic amino acids. SLC7-N2 possesses 14 transmembrane domains and exhibits particularly high affinity to arginine, thus we named it CATS (cationic amino acid transporter 5). CATS is expressed in the syncytio-trophoblast of mouse placenta and supposed to mediate transport of amino acids through the placental barrier as well as to supply placental cells with arginine as a precursor of NO synthesis. SLC7-N3 also possesses 14 transmembrane domains and transports small neutral amino acids as well as small basic amino acids, thus we have named it y^+Asc-1. In this study, the function of all the members of heterodimeric amino acid transporter family has been revealed. The results of this study would provide essential information to establish the basis for the genome-wide analyses of diseases or pathological conditions and facilitate drug design targeting the transporters of interest.

异二聚体氨基酸转运蛋白是由一个十二跨膜蛋白（催化亚基）和一个跨膜蛋白（调节亚基）的二硫键结合形成的。我们使用LAT 1、BAT 1和CAT 1的氨基酸序列作为查询，对人类和小鼠基因组数据库进行了BLAST搜索。我们发现了5个新基因，SLC 7-N1-N5，它们是SLC 7家族的新成员。通过对EST数据库的检索，我们发现其中两个基因（SLC 7-N4和SLC 7-N5）是假基因，因为它们从未出现在EST数据库中。SLC 7-N1具有12个跨膜结构域，被认为是异源二聚体氨基酸转运蛋白的催化亚基。我们将其命名为AGT-1。AGT-1蛋白存在于小鼠肾脏近端和远端小管的基底外侧膜上。由于AGT-1被认为与未知的调节亚基连接，我们已经产生了融合蛋白，其中AGT-1与已知的调节亚基4F 2 hc或rBAT连接，并在非洲爪蟾卵母细胞中表达它们。融合蛋白出现在质膜上，并表现出酸性氨基酸的转运。SLC 7-N2具有14个跨膜结构域，对精氨酸具有很高的亲和力，因此我们将其命名为CATS（阳离子氨基酸转运蛋白5）。CATS在小鼠胎盘的合胞体滋养层中表达，并且应该介导氨基酸通过胎盘屏障的转运，以及向胎盘细胞供应精氨酸作为NO合成的前体。SLC 7-N3还具有14个跨膜结构域，并转运小的中性氨基酸和小的碱性氨基酸，因此我们将其命名为y^+Asc-1。本研究揭示了异二聚体氨基酸转运蛋白家族所有成员的功能。这项研究的结果将提供必要的信息，以建立疾病或病理条件的全基因组分析的基础，并促进药物设计靶向感兴趣的转运蛋白。