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Functional analysis of the brain-specific LDL receptor family memners

脑特异性 LDL 受体家族成员的功能分析

基本信息

批准号：
09671027
负责人：
BUJO Hideaki
金额：
$ 2.05万
依托单位：
CHIBA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
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

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 humans, mice and chicken. This membrane receptor, termed LR1 1 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. Cytoplasmic signature sequences define the receptor as competent for endocytosis. The most striking properties of LR1 1s 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 … More rabbit and man ; (ii) lack of regulation by cholesterol and estrogen ; and (iii) expression in brain. The predominant expression of LR1 1 in brain and the presence of elements found in neural adhesion molecules suggested a function(s) in the central nervous system. In order to gain information about this complex receptor in an accessible system, we investigated its detailed localization and developmental expression pattern. Neuronal bodies such as Purkinje cells in the cerebellum and other neurons in the hippocampal formations and the cerebral cortex were particularly rich in LR1 1 transcripts. The developmental pattern of LR1 1 expression in brain, is in contrast to those of two other LDLR family members. During early development, murine LR1 1 expression levels are highly dependent on neural cell types. These findings are compatible with function(s) of LR1 1 in neural organization, and possibly, pathogenesis of degenerative brain diseases. In addition, detailed knowledge of LR1 1's biology will help to elucidate the roles of other mosaic proteins that share with LR1 1 elements whose function are not yet known. Less

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，除了其他组织外，其成员也在大脑中表达。为了支持这一概念，我们现在发现了来自人类、小鼠和鸡这两个不同物种的这一新兴分支的代表的表达并描绘了分子结构。这种膜受体被称为 LR1 1，迄今为止仅存在于兔子中，是一种复杂的七结构域嵌合蛋白，除其他结构元件外，还包含一簇 11 个 LDLR 配体结合重复序列和一个与 VPS 10（一种用于液泡蛋白分选的酵母受体）同源的结构域。细胞质特征序列将受体定义为具有内吞作用。 LR1 1 最显着的特性是它们 (i) 高度的结构保守性（在哺乳动物和鸟类中超过 80% 的同一性），在兔子和人的跨膜域和细胞质域中具有 100% 的同一性； (ii) 缺乏胆固醇和雌激素的调节； (iii)大脑中的表达。 LR1 1 在大脑中的主要表达以及神经粘附分子中发现的元素的存在表明了中枢神经系统的功能。为了在可访问的系统中获得有关这种复杂受体的信息，我们研究了其详细的定位和发育表达模式。神经元体，例如小脑中的浦肯野细胞以及海马结构和大脑皮层中的其他神经元，LR1 1 转录本特别丰富。 LR1 1 在大脑中表达的发育模式与其他两个 LDLR 家族成员的发育模式相反。在早期发育过程中，小鼠 LR1 1 表达水平高度依赖于神经细胞类型。这些发现与 LR1 1 在神经组织中的功能相一致，并且可能与退行性脑疾病的发病机制相一致。此外，对LR1 1 生物学的详细了解将有助于阐明与功能尚不清楚的LR1 1 元件共享的其他嵌合蛋白的作用。较少的