Identification and functional analysis of the LDL receptor gene family members

属于低密度脂蛋白受体基因家族的受体在许多物种的细胞内吞作用中发挥着关键作用，这些配体包括失效的、生物活性不活跃的和/或不需要的血浆载体复合体、某些毒素、蛋黄前体以及循环血浆脂蛋白。我们现在已经发现并鉴定了一个新的多结构域蛋白，并将其归类为低密度脂蛋白受体基因家族的成员。-250 kDa的膜蛋白命名为LR11，包含11个低密度脂蛋白受体配体结合重复序列，5个低密度脂蛋白受体“YWTD”重复序列，神经细胞黏附分子中发现的一个大的六足动物结构域，以及一个与用于空泡蛋白分类的酵母受体VPS10相似的结构域。细胞质结构域表现出典型的内吞功能涂层凹坑受体的特征。这种镶嵌的，可能是多功能的受体在大脑、肝脏和肾上腺中大量表达。LR11转基因细胞的配体印迹分析表明，LR11可与载脂蛋白E等脂蛋白结合，也可与低密度脂蛋白受体基因家族的其他成员结合。与低密度脂蛋白受体不同的是，高脂血症不影响兔肝脏的mRNA水平。目前，我们还不知道哪个配体(S)可能是LR11的真正生理伴侣(S)。然而，兔LR11在海马区、齿状回和大脑皮层的定位表明，LR11在大脑代谢活跃的区域具有功能意义。LR11新颖的复杂镶嵌结构为LDLR基因家族的进化和多功能提供了新的线索。

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.