Functional analysis of the brain-specific LDL receptor family memners

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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