Abstract
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor belong to the low density lipoprotein receptor family and bind apolipoprotein E. These receptors interact with the clathrin machinery to mediate endocytosis of macromolecules but also interact with other adapter proteins to perform as signal transduction receptors. The best characterized signaling pathway in which ApoER2 and VLDL receptor (VLDLR) are involved is the Reelin pathway. This pathway plays a pivotal role in the development of laminated structures of the brain and in synaptic plasticity of the adult brain. Since Reelin and apolipoprotein E, are ligands of ApoER2 and VLDLR, these receptors are of interest with respect to Alzheimer’s disease. We will focus this review on the complex structure of ApoER2 and VLDLR and a recently characterized ligand, namely clusterin.
Highlights
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor (VLDLR) belong to the low density lipoprotein receptor (LDLR) family, a class of type-I transmembrane receptors with high homology to their name-giving member the LDL receptor
Their role in the Reelin signaling pathway was nicely demonstrated in mice lacking ApoER2 and VLDLR
The loss of both receptors leads to a Reeler/Disabled-like phenotype in mice that is characterized by changes in the architecture of laminated structures in the brain [1,2]
Summary
Apolipoprotein E receptor 2 (ApoER2) and VLDL receptor (VLDLR) belong to the low density lipoprotein receptor (LDLR) family, a class of type-I transmembrane receptors with high homology to their name-giving member the LDL receptor. Besides more distant members of this family, such as LRP 1, 1b, 2, 5, and 6; ApoER2, VLDLR, and LDLR have a superimposable structure indicating that the corresponding genes may have evolved from one single ancestor by gene duplication events and minor exon rearrangements The architecture of these proteins (Figure 1) is characterized by six structural modules: (1) A N-terminal ligand binding domain with a variable number of LDL receptor type A repeats (LA repeats), (2) an invariant number of three epidermal growth factor (EGF) precursor-like repeats (type B repeats), (3) a YWTD β-propeller, (4) an O-linked sugar domain (OLSD), (5) a transmembrane domain, and (6) a cytoplasmic domain containing the NPXY motif that mediates clathrin-mediated endocytosis of these receptors and the interaction with other proteins rendering ApoER2 and VLDLR to signal transduction receptors as well. The loss of both receptors leads to a Reeler/Disabled-like phenotype in mice that is characterized by changes in the architecture of laminated structures in the brain [1,2]
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