LRP-1 and LRP-2 receptors function in the membrane neuron. Trafficking mechanisms and proteolytic processing in Alzheimer's disease

Abstract

Low density lipoprotein receptor-related protein (LRP) belongs to the low-density lipoprotein receptor family, generally recognized as cell surface endocytic receptors, which bind and internalize extracellular ligands for degradation in lysosomes. Neurons require cholesterol to function and keep the membrane rafts stable. Cholesterol uptake into the neuron is carried out by ApoE via LRPs receptors on the cell surface. In neurons the most important are LRP-1 and LRP-2, even it is thought that a causal factor in Alzheimer's disease (AD) is the malfunction of this process which cause impairment intracellular signaling as well as storage and/or release of nutrients and toxic compounds. Both receptors are multifunctional cell surface receptors that are widely expressed in several tissues including neurons and astrocytes. LRPs are constituted by an intracellular (ICD) and extracellular domain (ECD). Through its ECD, LRPs bind at least 40 different ligands ranging from lipoprotein and protease inhibitor complex to growth factors and extracellular matrix proteins. These receptors has also been shown to interact with scaffolding and signaling proteins via its ICD in a phosphorylation-dependent manner and to function as a co-receptor partnering with other cell surface or integral membrane proteins. Thus, LRPs are implicated in two major physiological processes: endocytosis and regulation of signaling pathways, which are both involved in diverse biological roles including lipid metabolism, cell growth processes, degradation of proteases, and tissue invasion. Interestingly, LRPs were also localized in neurons in different stages, suggesting that both receptors could be implicated in signal transduction during embryonic development, neuronal outgrowth or in the pathogenesis of AD.

Keywords: Alzheimer's disease; LRP-1; LRP-2; amyloid-beta; astrocytes; brain; central nervous system; intracellular domain; megalin; neurodegenerative diseases; neuron.

Figure 1

Schematic domain organization of LRP1. The LRP1 contains five different domains: (A) the ligand-binding domain, (B) the EGF-precursor homology domain, (C) the O-linked sugar domain, (D) the transmembrane domain and (E) the intracellular domain. The ligand-binding domain consists of four clusters and mediates the binding to ligands (see Table 1). The hydrophobic transmembrane domain ensures the anchoring the LRP1 in the plasma membrane. The cytoplasmic tail of the LRP1 containing the characteristic NPXY sequence interact with phospho-tyrosine binding domains of cellular adaptors proteins which are important for endocytosis and subsequent intracellular transport. The LRP1 is proteolytically cleaved within the Golgi complex to generate two subunits: (A) the N-terminal 515-kDa α-subunit containing the ligand-binding domains and (B) the C-terminal 85-kDa β-subunit containing an extracellular part, the transmembrane spanning domain and the cytoplasmic intracellular domain. The cytoplasmatic LRP1 α-subunit contains diverse potential endocytosis and signaling motifs: two NPXY motifs whereas the distal NPXY sequence overlaps with the endocytosis signal XYYL and two dileucine motifs. With arrows is indicating the cleavage events in the molecule and the resulting fragments.

Figure 2

LRP2 is structurally similar to LRP1. The ECD of LRP2 contains four clusters (1–4) of lipoprotein receptor ligand-binding repeats, growth factor repeats, an EGF repeat, and YWTD spacer regions. Interestingly, the second cluster has been identified as a common binding site for several ligands including Apo E, Apo M, retinol binding protein and transthyretin. The fourth cluster has been identified as binding site for Aβ. The LRP2 is also proteolytically cleaved to generate two subunits: (A) the N-terminal (soluble LRP2) containing the ligand-binding domains and (B) the C-terminal subunit containing an extracellular fragment (CTF), the transmembrane spanning domain and the ICD. The ICD contains diverse potential endocytosis and signaling motifs. The ICD binds adaptor proteins important for LRP2-mediated endocytoses, such as Dab2 and is able to induce intracellular events such as RIP signaling. The cytoplasmic domain of LRP2 has several putative internalization motifs, including one dileucine and three NPxY motifs. In addition, it contains two proline-rich sequences, one PDZ terminal motif, several putative protein kinase C and casein kinase II phosphorylation motifs as well as one protein kinase A phosphorylation motif. Under basal conditions, these motifs contribute little to the phosphorylation of the LRP2 cytoplasmic domain. Although there are few evidences about the cytoplasmic regulation of LRP1 and LRP2, the mechanism is conserved in the gene evolution and probably the regulation and trafficking of both receptors in neurons are very similar. With arrows is indicating the cleavage events in the molecule and the resulting fragments.