The Reelin Receptors Apolipoprotein E receptor 2 (ApoER2) and VLDL Receptor

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.

Keywords: Alzheimer’s disease; VLDL receptor; apolipoprotein E receptor 2; clusterin; reelin.

Figure 1

Structures of low density lipoprotein receptor (LDLR), VLDL receptor (VLDLR), and Apolipoprotein E receptor 2 (ApoER2). The LDL receptor and its closest relatives VLDL receptor and ApoER2 are composed of six characteristic superimposable structural modules: (1) ligand binding domain with a variable number of LDL receptor type A repeats (LA repeats), (2) epidermal growth factor precursor-like repeats A, B, and C (EGF repeats), (3) a YWTD containing domain forming a so-called β-propeller, (4) the O-linked sugar domain (OLSD), (5) a transmembrane domain, and (6) a cytoplasmic domain containing the NPXY motif and facultatively a proline-rich domain unique for ApoER2. Domains are not drawn to scale.

Figure 2

ApoER2 variants present in human, mouse, and chicken. ApoER2 transcript/exon organizations for human and mouse are presented as rectangular bars with exon numbers noted below. Corresponding protein domains are depicted inside the boxes (LDL receptor type A repeats, LA; epidermal growth factor precursor-like repeats, A–C; O-linked sugar domain, OLSD; proline-rich region). Structural domains that are not corresponding to single exons are delineated above the rectangular bar (transmembrane domain; TM). Alternatively spliced exons are indicated by V. Domain-structures of the corresponding proteins are shown below the gene structure. Hatched domains can be deleted from receptor variants by alternative splicing. Domains are not drawn to scale.

Figure 3

VLDLR variants present in human, mouse, and chicken. VLDLR transcript/exon organizations for human and mouse are presented as rectangular bar with exon numbers noted below. Corresponding protein domains are depicted inside the boxes (LDL receptor type A repeats, LA; epidermal growth factor precursor-like repeats, A–C; O-linked sugar domain, OLSD). Structural domains which are not corresponding to single exons are delineated above the rectangular bar (transmembrane domain; TM). Alternatively spliced exons are indicated by V. Domain-structures of the corresponding proteins are shown below the gene structure. Hatched domains can be deleted from receptor variants by alternative splicing. Domains are not drawn to scale.

Figure 4

Proteins interacting with VLDLR and/or ApoER2. Proteins interacting only with ApoER2 are indicated in the boxes on the right side of the scheme; proteins interacting only with VLDL receptor are indicated in the boxes on the left side of the scheme; proteins interacting with both receptors are indicated in between the two receptors. Receptor ligands are indicated in the red boxes. Interacting receptors/transmembrane proteins are indicated in the grey boxes. Intracellular adapter proteins are indicated in the blue boxes.