Lipoprotein receptors – an evolutionarily ancient multifunctional receptor family

Abstract

Lipoprotein receptors are evolutionarily ancient proteins that are expressed on the surface of many cell types. Beginning with the appearance of the first primitive multicellular organisms several structurally and functionally distinct families of lipoprotein receptors evolved. Originally, these cell surface proteins were thought to merely mediate the traffic of lipids and nutrients between cells and in some cases, by functioning as scavenger receptors, remove other kinds of macromolecules, such as proteases and protease inhibitors from the extracellular space and the cell surface. Over the last decade, this picture has greatly expanded. We now appreciate that many of these receptors are not mere cargo transporters; they are deeply embedded in the machinery by which cells communicate with each other. By physically interacting and coevolving with fundamental signaling pathways, lipoprotein receptors have occupied essential and surprisingly diverse functions that are indispensable for integrating the complex web of cellular signal input during development and in differentiated tissues. Furthermore, lipoprotein receptors modulate cellular trafficking and localization of the amyloid precursor protein (APP) and the β-amyloid peptide (Aβ), suggesting a role in the pathogenesis of Alzheimer’s disease. Moreover, compelling evidence shows that low density lipoprotein receptor family members are involved in tumor development and progression.

Site-specific O-glycosylation of members of the low-density lipoprotein receptor superfamily enhances ligand interactions

“…The low-density lipoprotein receptor (LDLR) and related receptors are membrane-bound cell surface receptors with important endocytic functions for lipoproteins and a variety of diverse extracellular ligands (1). The founding member LDLR is important for maintaining cholesterol homeostasis, and deleterious mutations in LDLR lead to decreased LDL catabolism and elevated levels of plasma LDL-cholesterol (LDL-C) (2).…”

“…The founding member LDLR is important for maintaining cholesterol homeostasis, and deleterious mutations in LDLR lead to decreased LDL catabolism and elevated levels of plasma LDL-cholesterol (LDL-C) (2). The LDLR superfamily includes the VLDL receptor (VLDLR), LDLR-related protein 1 (LRP1), LDLR-related protein 1B (LRP1B), LDLR-related protein 2 (LRP2 or megalin) and LDLR-related protein 8 (LRP8 or ApoER2), as well as more distantly related receptors such as the Sortilin-related receptor (SORLA) (1). These members also have important roles in cardiovascular diseases as well as neurodegenerative and proteinuric renal diseases (3)(4).…”

“…These members also have important roles in cardiovascular diseases as well as neurodegenerative and proteinuric renal diseases (3)(4). The ectodomains of LDLR-related proteins share characteristic structural features including LDLR-type A repeats (LA) (complement-like cysteine-rich ligand binding repeats), EGF-like repeats, and YWTD beta-propeller domains (1).…”

Ligand-induced Homotypic and Heterotypic Clustering of Apolipoprotein E Receptor 2

“…APP and its homologues share a number of both extracellular and intracellular interacting proteins with the family of lipoprotein receptors containing ApoER2 and VLDLR (77). Both families are type I transmembrane proteins with signaling functions.…”

Factor VIII Interacts with the Endocytic Receptor Low-density Lipoprotein Receptor-related Protein 1 via an Extended Surface Comprising “Hot-Spot” Lysine Residues

“…The low-density lipoprotein receptor family is an ancient family of transmembrane receptors regulating diverse biological processes ranging from lipoprotein metabolism to blood coagulation (1)(2)(3). Members of the LDL receptor family are able to interact with an unusual number of ligands; e.g.…”