Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.
Structure ApoER2 is a protein made up of 870 amino acids. It is separated into a ligand binding domain of eight ligand binding regions, an EGF-like domain containing three cysteine-rich repeats, an O-linked glycosylation domain of 89 amino acids, a transmembrane domain of 24 amino acids, and a cytoplasmic domain of 115 amino acids, including an NPXY motif.
Each letter in the NPXY motif represents a certain amino acid where N is arginine, P is proline, X is any amino acid, and Y is tyrosine.
Cytoplasmic tail All LDL receptor family proteins contain a cytoplasmic tail with at least one NPXY motif. This motif is important for binding intracellular adapter proteins and endocytosis. ApoER2 is distinct from most other members of the LDL family of receptors due to a unique insert on its cytoplasmic tail. In ApoER2, there is a proline-rich 59 amino acid insert encoded by the alternatively spliced exon 19. This insert allows for protein interactions that are unable to occur with other LDL receptors. It binds the PSD-95 adapter protein, cross-linking ApoER2 and the NMDA receptors during the process of long-term potentiation, and is also bound specifically by JIP-2, an important interaction in the JNK signalling pathway. It is also speculated that this insert may diminish the function of ApoER2 in lipoprotein endocytosis by somehow disrupting the NPXY motif.
Function
Reelin/Dab1 signalling pathway ApoER2 plays a critical role as a receptor in the reelin signalling pathway, which is important for brain development and postnatal function of the brain. This pathway specifically affects cortical migration and long-term potentiation.
Cortical migration In development, reelin is secreted by Cajal-Retzius cells. Reelin acts as an extracellular ligand binding to ApoER2 and VLDLR on migrating neurons. A specific lysine residue on reelin binds to the first repeat on the ligand binding domain of ApoER2. This interaction with the two receptors activates intracellular processes that begin with the phosphorylation of Dab1, a tyrosine kinase phosphorylated protein which is encoded by the DAB1 gene. This protein associates with the NPXY motifs on the intracellular tails of ApoER2 and VLDLR. Upon reelin binding, Dab1 is phosphorylated by two tyrosine kinases, Fyn and Src. The phosphorylated Dab1 then causes further activation of these two kinases and others, including a phosphatidylinositol-3-kinase (PI3K). PI3K activation leads to inhibitory phosphorylation of the tau kinase glycogen synthase kinase 3 beta (GSK3B), which alters the activity of tau protein, a protein involved in stabilizing microtubules. This transduction is combined with the activation of other pathways that influence the cytoskeletal rearrangement necessary for proper cortical cell migration. The result of proper neuronal migration through the cortical plate (CP) is an inside-out arrangement of neurons, where the younger neurons migrate past the older neurons to their proper locations. Studies in reeler mutant mice show that knocking out the reeler gene results in aberrant migration as well as outside-in layering, in which younger neurons are unable to travel past the older ones. Such abnormal layering is also seen in VLDLR−apoER2− and dab1- mutants, indicating the importance of this entire pathway in cortical migration of the developing embryo. There is some confusion as to the exact function of the reelin-signalling pathway in the process of cortical migration. Some studies have shown that reelin release is necessary for the initiation of cell movement to its proper location, whereas others have shown that it is part of the process of terminating migration. These conflicting results have led researchers to speculate that it plays a role in both processes through interactions with different molecules at different stages of neuronal migration.
Long-term potentiation After development, reelin is secreted in the cortex and hippocampus by gamma-aminobutyric acid-ergic interneurons. Through binding of ApoER2 in the hippocampus, it plays a role in the NMDA receptor activation that is required for long-term potentiation, a mechanism by which two neurons gain a stronger, longer-lasting transmission due to simultaneous firing. The increased synaptic plasticity associated with this process is essential in development of memory and spatial learning. Studies with mice have shown less expression of ApoER2 leads to impaired spatial learning, fear conditioned learning, and a mild disruption to the hippocampus. In the hippocampus, ApoER2 is complexed with NMDA receptors through the PSD-95 adapter protein. When reelin binds ApoER2, it initiates tyrosine phosphorylation of NMDA receptors. This occurs through Dab-1 activation of Src family kinases, which have been shown to play a role in regulating synaptic plasticity. VLDLR also acts as a receptor coupled to ApoER2 as it does during development, but its role is not well understood. ApoER2 plays a more important role in this process, most likely due to its ability to bind the PSD-95 adapter protein through the 59 amino acid insert on its cytoplasmic tail. Studies with mice have shown that knocking out ApoER2 or just the alternatively spliced exon 19 causes a much greater impairment of LTP than knocking out VLDLR.
Lipoprotein endocytosis ApoER2 is a major receptor for apolipoprotein E in the brain and is involved in the endocytosis of lipoproteins there.
Other interacting proteins
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