Functional analysis of the brain-specific LDL receptor family memners

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类、小鼠和鸡的分子结构。这种膜受体，称为LR 11，迄今为止仅已知存在于兔中，是一种复杂的七结构域镶嵌蛋白，除了其他结构元件外，还含有一簇11个LDLR配体结合重复序列和与VPS 10（一种用于液泡蛋白分选的酵母受体）同源的结构域。胞质标签序列将受体定义为有能力进行内吞作用。LR 11最引人注目的特性是它们的（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LR 11的跨膜和胞质结构域中具有100%的同一性。 ...更多信息 兔和人;（ii）缺乏胆固醇和雌激素的调节;和（iii）在脑中的表达。LR 11在脑中的主要表达和在神经粘附分子中发现的元件的存在表明在中枢神经系统中的功能。为了在一个可及的系统中获得关于这个复杂受体的信息，我们研究了它的详细定位和发育表达模式。神经元体如小脑中的浦肯野细胞和海马结构和大脑皮层中的其他神经元特别富含LR 11转录物。LRll在脑中表达的发育模式与其他两种LDLR家族成员的发育模式相反。在早期发育期间，鼠LR 11表达水平高度依赖于神经细胞类型。这些发现与LR 11在神经组织中的功能一致，并且可能与退行性脑疾病的发病机制一致。此外，详细了解LR 11的生物学将有助于阐明与LR 11元件共享的其他嵌合蛋白的作用，这些嵌合蛋白的功能尚不清楚。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