Molecular analysis of the LDL receptor gene family members

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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 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.