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Identification and functional analysis of the LDL receptor gene family members

LDL受体基因家族成员的鉴定及功能分析

基本信息

批准号：
07557177
负责人：
SAITO Yasushi
金额：
$ 4.67万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07557177/
关键词：
gene family LDL receptor cloning cDNA apo (protein) E multifunctionality

项目摘要

Receptors belonging to the LDL receptor gene family are playing key roles for wide varied species in cellular endocytosis of a broad spectrum of ligands including spent, biologically inactive and/or unwanted plasmatic carrier complexes, certain toxins, yolk precursors, as well as circulating plasma lipoproteins. We now have discovered and characterized a novel multidomain protein and classified it as a member of the LDL receptor gene family. The -250kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a rgoup of 5 LDL receptor "YWTD" repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, liver and adrenal glands. Ligand blotting of LR11-transfected cells demonstrated that LR11 binds apolipoproteinE-containing lipoproteins, as well as other members of LDL receptor gene family. In contrast to the LDL receptor, the mRNA levels in rabbit liver is unaffected by hyperlipidemia. At present, we have no idea which ligand (s) may be the true physiological partner (s) of LR11. However, the localization of rabbit LR11 in the hippocampus, dentate gyrus and cerebral cortex suggests functional significance of LR11 in metabolically active regions of brain. The novel complex mosaic structure of LR11 sheds new lights on the evolution and proposed multifunctionality of the LDLR gene family.

属于LDL受体基因家族的受体在细胞内吞广谱配体（包括用过的、生物学上无活性的和/或不需要的血浆载体复合物、某些毒素、蛋黄前体以及循环血浆脂蛋白）中对各种物种起关键作用。我们现在已经发现并鉴定了一种新的多结构域蛋白，并将其归类为LDL受体基因家族的一员。约250 kDa的膜蛋白，称为LR 11，包含11个LDL受体配体结合重复序列的簇，5个LDL受体“YWTD”重复序列的rgup，神经细胞粘附分子中发现的结构元件的大的六重结构域，以及与用于液泡蛋白分选的酵母受体VPS 10相似的结构域。胞质结构域表现出典型的内吞能力的包被的小坑受体的功能。镶嵌的，可能是多功能的，受体在脑，肝和肾上腺中大量表达。LR 11转染细胞的配体印迹表明，LR 11结合载脂蛋白E的脂蛋白，以及LDL受体基因家族的其他成员。与LDL受体相反，兔肝脏中的mRNA水平不受高脂血症的影响。目前，我们还不知道哪种配体可能是LR 11的真正生理伴侣。然而，兔LR 11在海马、齿状回和大脑皮质中的定位表明LR 11在脑的代谢活性区域中具有功能意义。LR 11的新的复杂镶嵌结构为LDLR基因家族的进化和提出的多功能性提供了新的线索。