Molecular analysis of the LDL receptor gene family members

低密度脂蛋白受体（LDLR）基因家族的某些受体似乎构成了一个新发现的分支，其成员除了在其他组织中表达外，还在大脑中表达。为了支持这一观点，我们现在已经从人和鸡这两个如此不同的物种中发现了这一新兴分支的一个代表的表达并描绘了其分子结构。这种膜受体被称为LR11，迄今为止只存在于兔子体内，是一种复杂的7结构域镶嵌蛋白，除其他结构元件外，它含有11个LDLR配体结合重复序列和一个与VPS 10同源的结构域，VPS 10是一种用于液泡蛋白分选的酵母受体。细胞质特征序列确定受体能胜任内吞作用。LR1基因最显著的特点是其高度的结构保守性（在哺乳动物和鸟类中同源性超过80%），在兔和人的跨膜结构域和细胞质结构域同源性为100%；（ii）缺乏胆固醇和雌激素的调节；（三）脑内表达。LR1的特征表明它在细胞间和细胞内的配体运输过程中起重要作用，其中某些作用可能与其他脑特异性LDLR家族成员共享。此外，我们报道在两种动物模型中，LR1在动脉粥样硬化过程中被显著诱导。免疫组织化学表明，LR11在内膜平滑肌细胞（SMCs）中诱导最高，其次是靠近动脉粥样硬化病变内膜边界的内侧SMCs。这些发现表明，在动脉硬化病变发展过程中，LR11的上调可能参与了内膜和内侧SMCs的病理作用，并首次揭示了这一有趣的LDLR家族成员尚不为人知的功能意义。

Certain receptors belonging to the low density lipoprotein receptor (LDLR) gene family appear to constitute a newly-identified branch whose members are expressed, in addition to other tissues, in brain. In support of this concept, we have now discovered the expression and delineated the molecular structures of a representative of this emerging branch from two such diverse species as man and chicken. This membrane receptor, termed LR11 and thus far only known to exist in the rabbit, is a complex seven-domain mosaic protein containing, among other structural elements, a cluster of 11 LDLR ligand binding repeats and a domain with homology to VPS 10, a yeast receptor for vacuolar protein sorting. Cytoplasniic signature sequences define the receptor as competent for endocytosis. The most striking properties of LR1 Is are their (i) high degree of structural conservation (over 80% identity among mammals and birds) with 100% identity in the membrane spanning and cytoplasmic domains of rabbit and man ; (ii) lack of regulation by cholesterol and estrogen ; and (iii) expression in brain. The features of LR1 1 suggest important roles in intercellular and intracellular ligand transport processes, certain of which it may share with other brain-specific LDLR family members. Furthermore, we report that LR1 1 is markedly induced during the process of atherogenesis in two animal models. Immunohistochemistry demonstrated that the highest induction of LR11 occurs in intimal smooth muscle cells (SMCs), followed by medial SMCs close to the intimal border of the atheromatous lesions. These findings suggest that up-regulation of LR11 might be contributing to the pathological roles of intimal and medial SMCs during arteriosclerotic lesion development, and provide the first insight into the yet unknown functional significance of this intriguing LDLR family member.