Molecular analysis of the LDL receptor gene family members

属于低密度脂蛋白受体(LDLR)基因家族的某些受体似乎构成了一个新发现的分支，其成员除在其他组织中表达外，还在大脑中表达。为了支持这一概念，我们现在已经发现了来自人和鸡这两个不同物种的这一新兴分支的一个代表的表达和分子结构。这种膜受体被称为LR11，到目前为止只在兔体内存在，是一个复杂的七个结构域的嵌合体蛋白，除了其他结构元素外，还包含一个由11个LDLR配体结合重复序列组成的簇，以及一个与VPS 10同源的结构域，VPS 10是一种用于空泡蛋白分离的酵母受体。细胞质特征序列定义受体具有内吞作用的能力。LR1最显著的特征是：(1)高度的结构保守性(哺乳动物和鸟类的同源性超过80%)，在兔和人的膜跨区和细胞质区域有100%的同源性；(Ii)不受胆固醇和雌激素的调节；(Iii)在脑中表达。LR11的功能提示它在细胞间和细胞内的配体运输过程中发挥重要作用，其中某些可能与其他脑特异性LDLR家族成员共享。此外，我们还报道了在两种动物模型中，LR11在动脉粥样硬化形成过程中被显著诱导。免疫组织化学显示，LR11在动脉粥样硬化性病变的内膜平滑肌细胞中的诱导率最高，其次是接近内膜边界的中膜平滑肌细胞。这些发现表明，LR11的上调可能参与了动脉粥样硬化病变发展过程中内膜和中膜SMC的病理作用，并首次揭示了这个有趣的LDLR家族成员尚不清楚的功能意义。

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.