Functional analysis of the brain-specific LDL receptor family memners

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。为了支持这一概念，我们现在已经从人类、老鼠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LR1 1，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 - 1最显著的特性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%），在跨膜和细胞质结构域的同源性为100%。（ii）缺乏胆固醇和雌激素的调节；（三）脑内表达。LR1在脑中的主要表达以及在神经粘附分子中发现的元素的存在表明其在中枢神经系统中起作用。为了在可及系统中获得有关该复杂受体的信息，我们研究了其详细的定位和发育表达模式。小脑中的浦肯野细胞等神经元体以及海马体和大脑皮层中的其他神经元尤其富含LR1转录本。LR1在脑内表达的发育模式与LDLR家族其他两种成员的发育模式不同。在发育早期，小鼠LR1的表达水平高度依赖于神经细胞类型。这些发现与LR1在神经组织中的功能，并可能与退行性脑疾病的发病机制相一致。此外，对LR1生物学的详细了解将有助于阐明与LR1共享的其他功能尚不清楚的马赛克蛋白的作用。少

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