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Molecular analysis of the LDL receptor gene family members

LDL受体基因家族成员的分子分析

基本信息

批准号：
09044258
负责人：
SAITO Yasushi
金额：
$ 2.82万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for international Scientific Research
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044258/
关键词：
gene family LDL receptor LR11 brain atheroscleosis

项目摘要

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.

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鉴定的分支，其成员除了在其他组织中表达外，还在脑中表达。为了支持这一概念，我们现在已经发现了这一新兴分支的一个代表的表达，并描绘了来自两个不同物种如人和鸡的分子结构。这种膜受体，称为LR 11，迄今为止只知道存在于兔中，是一种复杂的七结构域镶嵌蛋白，除其他结构元件外，还含有一簇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。胞质标签序列将受体定义为有能力进行内吞作用。LRlIs最显著的特性是它们的（i）高度结构保守性（在哺乳动物和鸟类中超过80%的同一性），在兔和人的跨膜和胞质结构域中具有100%的同一性;（ii）缺乏胆固醇和雌激素的调节;和（iii）在脑中表达。LR 11的特征表明在细胞间和细胞内配体转运过程中的重要作用，其中某些可能与其他脑特异性LDLR家族成员共享。此外，我们报告，LR 11显着诱导过程中的动脉粥样硬化在两种动物模型。免疫组化显示，LR 11的最高诱导发生在内膜平滑肌细胞（SMC），其次是接近动脉粥样硬化病变内膜边界的中膜SMC。这些发现表明，LR 11的上调可能有助于动脉粥样硬化病变发展过程中内膜和中膜SMC的病理作用，并首次深入了解这个有趣的LDLR家族成员的未知功能意义。