Human Apolipoprotein E Receptor 2

Abstract

Isolation and characterization of a human cDNA demonstrated a novel lipoprotein receptor designated apolipoprotein E receptor 2 (apoER2). The new receptor consists of five functional domains resembling the low density lipoprotein (LDL) and very low density lipoprotein (VLDL) receptors. LDL receptor deficient Chinese hamster ovary cells expressing human apoER2 bound apoE rich ␤-migrating VLDL with high affinity and internalized. LDL was bound with much lower affinity to these cells. The 4.5-and 8.5-kb mRNAs for the receptor were most highly expressed in human brain and placenta. In rabbit tissues, multiple species of the mRNA with 4, 4.5, 5.5, 8.5, and 11 kb were detected most intensely in brain and testis and, to a much lesser extent, in ovary, but were undetectable in other tissues. In rat adrenal pheochromocytoma PC12 cells, the receptor mRNA was induced by treatment of the cells with nerve growth factor. The receptor transcripts were detectable most intensely in the cerebellar cortex, choroid plexus, ependyma, hippocampus, olfactory bulb and, to a much lesser extent, in the cerebral cortex as revealed by in situ hybridization histochemistry. In the cerebellar cortex, the receptor transcripts were densely deposited in Purkinje cell somata.Receptor-mediated endocytosis of plasma lipoproteins plays an important role in the metabolism of cholesterol and triglyceride in the body. The low density lipoprotein (LDL) 1 receptor, one of the best characterized cell surface receptors, mediates cholesterol homeostasis in the body (1). The LDL receptor binds apolipoprotein B-100 containing LDL and apolipoprotein E (apoE)-containing lipoproteins, whereas the recently found very low density lipoprotein (VLDL) receptor binds only apoEcontaining lipoproteins (2, 3). Both the LDL receptor (4 -7) and VLDL receptor (2, 8 -14) consist of five functional domains: (i) an amino-terminal ligand binding domain composed of multiple cysteine-rich repeats; (ii) an epidermal growth factor (EGF) precursor homology domain, which mediates the acid-dependent dissociation of the ligands from the LDL receptor (15); (iii) an O-linked sugar domain; (iv) a transmembrane domain; and (v) a cytoplasmic domain with a coated pit targeting signal (16). Genetic deficiencies of the LDL receptor give rise to familial hypercholesterolemia, one of the most common genetic diseases in humans (17). Mutations in the chicken VLDL receptor gene lead to the failure to produce offspring (13, 18).Lipoprotein metabolism in the central nervous system (CNS) has been poorly understood, despite the importance of lipids in some specialized neural membranes, such as myelin. Most of lipids in the CNS are actively synthesized in the CNS itself and deposited in large amounts during the early phase of development (19, 20). The rate of cholesterol and fatty acid synthesis in the brain is high during the myelinating period and declines thereafter (19,20). Although most of lipids in the brain are believed to be synthesized within the brain itself, small amounts of cholesterol (21)...

v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1

“…This is consistent with recent work showing that two other LDL receptor-related proteins, the ApoE receptor 2 and the VLDL receptor, are involved in relaying guidance cues to migrating neurons during development (Trommsdorff et al, 1999). Both the ApoE receptor 2 and the VLDL receptor contain a single N-P-X-Y motif in their cytoplasmic domain that may function as a binding site for disabled (DAB) (Takahashi et al, 1992;Kim et al, 1996;Howell et al, 1999). DAB is a PTB domain-containing adaptor protein that is expressed primarily in the nervous system (Howell et al, 1997).…”

Essential Role of the Apolipoprotein E Receptor-2 in Sperm Development

“…Apolipoprotein (apo) E receptor-2 (apoER2) 1 is a member of the low density lipoprotein (LDL) receptor gene family and a prototype receptor that acts both in endocytosis and in signal transduction (1)(2)(3)(4). In particular, apoER2 functions as a cellular receptor for Reelin, a signaling factor that regulates neuronal migration processes in the embryonic brain.…”

“…Aside from post-mitotic neurons in the brain, apoer2 transcripts are also abundant in the placenta, the ovaries, and the epididymis (1,3,10). The function of the receptor in these tissues, however, remains unclear.…”

Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)

“…LRP is a member of the LDL receptor family, which includes the LDL receptor (13), the VLDL receptor (14), gp330/megalin (15), and a newly described apolipoprotein E receptor 2 (16). A 39-kDa protein, termed the receptor-associated protein (RAP) (17), binds to several members of the LDL receptor family (18 -20) and blocks their ligand binding capacity.…”