[Frontiers in Bioscience 6, d417-428, March 1, 2001]

STRUCTURAL, BIOCHEMICAL AND SIGNALING PROPERTIES OF THE LOW-DENSITY LIPOPROTEIN RECEPTOR GENE FAMILY

M. Mahmood Hussain

Departments of Anatomy and Cell Biology, and Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY 11203

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Structural motifs and function
3.1. LDL receptor
3.2. LDL receptor-related protein
3.3. Megalin
3.4. VLDL receptor
3.5. ApoE receptor 2
3.6. LR11
3.7. Related receptors
4. Endocytic properties of the LDL-R gene family
4.1. Ligands of the gene family
4.2. Endocytosis of different ligands
5. Signaling by the LDL-R gene family in brain
6. Concluding remarks
7. Acknowledgements
8. References

1. ABSTRACT

The low-density lipoprotein (LDL) receptor (LDL-R) family members (LDL-R, LRP, megalin, VLDL-R, apoER2) bind several extra-cellular structurally dissimilar ligands and internalize them for degradation by lysosomes by a process called receptor-mediated endocytosis. The receptor-mediated endocytosis involves immobilization of circulating ligands onto the cell-surface followed by their internalization and degradation. All the receptors can perform both of these functions. However, in the majority of the cases, other proteins immobilize ligands on to the cell-surface and subsequent internalization is mediated by these receptors. The LDL-R and LRP play important roles in plasma cholesterol homeostasis and fetal development. Megalin is an antigenic determinant for Heymann nephritis in rats and may be important for re-absorption of various molecules by the kidney. VLDL-R homologue in chicken is essential for female fertility. This receptor and apoER2 are critical for the proper development of the brain in mice. The members of the LDL-R gene family contain several complement-type and EGF precursor-like repeats, and single transmembrane and cytoplasmic domain. Cysteine-rich complement-type repeats containing DxSDE sequences at the C-termini constitute ligand-binding domains. In contrast to the ligand binding domains, receptor-binding domains in different ligands do not share sequence homology. It has been proposed that positive electrostatic surface potentials, not the primary sequences, in different ligands constitute receptor-binding domains. The EGF precursor homology repeats in receptors are important for the dissociation of ligands from receptors in endocytic vesicles. The transmembrane domain is necessary for anchoring to membranes and the cytoplasmic domain is required for their targeting to coated pits and subsequent internalization. The receptor-mediated endocytosis involves recognition of the NPXY motif by clathrin. Recently, this motif has also been implicated in signaling pathways that are crucial in brain development. The signaling process involves the recognition of the NPXY motif by Disabled-1 protein and possibly other proteins involved in intracellular signaling cascade. The LDL-R gene family has provided important insights into the mechanisms of ligand catabolism and may serve as new targets for the treatment of different cardiovascular and neuronal disorders. In the future, their role in signaling may provide novel insights into brain development and neuronal layering.