LRP2 - LDL receptor related protein 2 |Elisa - Clia - Antibody - Protein

Background

Low-Density Lipoprotein Receptor-Related Protein 2 (LRP2), also known as megalin, is a large endocytic receptor primarily known for its role in cellular uptake of a wide variety of ligands. LRP2 belongs to the LDL receptor family and is highly expressed in epithelial cells, particularly in the proximal tubule cells of the kidneys, the choroid plexus of the brain, and the inner ear. By binding and internalizing various ligands, including lipoproteins, vitamins, hormones, and protein complexes, LRP2 is essential for nutrient reabsorption, hormonal balance, and cellular signaling.

LRP2’s functions are particularly significant in the kidneys, where it reabsorbs essential proteins and other molecules from the filtrate to prevent loss through urine. In the brain, it has roles in neurodevelopment and modulates responses to growth factors. LRP2’s complex functionality extends to embryonic development, where it influences morphogen signaling pathways critical to organ formation. Given its roles in various physiological systems, LRP2’s dysfunction or deficiency has been linked to developmental disorders, kidney disease, and metabolic syndromes.

Protein Structure

LRP2 is a massive protein, approximately 600 kDa, with a structure that is critical to its role as a multifunctional endocytic receptor. The protein comprises multiple structural domains that facilitate ligand binding, receptor dimerization, and endocytosis:

Extracellular Domain:

• The extracellular portion of LRP2 is composed of four primary ligand-binding domains (I-IV), which are arranged sequentially. Each domain contains clusters of cysteine-rich LDL receptor class A (LA) repeats that facilitate ligand binding. This design enables LRP2 to interact with a diverse range of ligands, such as retinol-binding protein, vitamin D-binding protein, albumin, and lipoproteins.
• Each ligand-binding domain is characterized by calcium-dependent interactions with its respective ligands, with each LA repeat requiring calcium ions to stabilize its conformation and mediate ligand interaction.
• Epidermal Growth Factor (EGF) domains and complement-type repeats (CR) are interspersed among the ligand-binding regions. These repeats are essential for stabilizing protein conformation and supporting the receptor's functional interactions with various ligands.
• Additional domains known as β-propeller domains act as modular binding sites that facilitate pH-dependent release of ligands within the endosome following endocytosis, aiding in efficient recycling of the receptor to the cell surface.

Transmembrane Domain:

• The transmembrane segment of LRP2 anchors the receptor within the plasma membrane, bridging the extracellular ligand-binding domains with the intracellular cytoplasmic tail.

Cytoplasmic Tail:

• The cytoplasmic region of LRP2 contains signaling motifs that regulate endocytic processes and intracellular trafficking. The tail has NPXY motifs essential for clathrin-mediated endocytosis, facilitating the formation of endocytic vesicles around ligand-bound LRP2.
• Adaptor proteins, such as Disabled-2 (Dab2), interact with these motifs to mediate receptor internalization and trafficking through endosomes.

Proteolytic Processing and Shedding:

• LRP2 undergoes proteolytic cleavage by γ-secretase, which releases an intracellular fragment that may influence gene expression by translocating to the nucleus. This cleavage mechanism further adds to LRP2’s regulatory complexity.

Classification and Subtypes

LRP2 is classified within the LDL receptor family, which includes other receptors like LRP1 and LRP3, characterized by their large size and modular domains enabling ligand-binding diversity. Though LRP2 does not have subtypes, it shares functional and structural similarities with LRP1, particularly in ligand-binding capacities and endocytic functions. However, its specificity for certain ligands, particularly in the renal and central nervous systems, distinguishes it from other LDL receptor family members.

Function and Biological Significance

LRP2 is essential in various physiological functions across several organ systems:

Endocytosis and Reabsorption in the Kidneys:

• In the kidneys, LRP2 is abundantly expressed on the apical surface of proximal tubule cells, where it functions to reabsorb essential nutrients, vitamins, and proteins from the filtrate, preventing their loss in urine. Ligands such as vitamin D-binding protein and albumin are internalized by LRP2, which ensures that these molecules are reclaimed and cycled back into circulation.
• LRP2’s role in kidney function is further exemplified by its impact on hormone reabsorption, including parathyroid hormone, contributing to the regulation of calcium homeostasis.

Neurodevelopment and Growth Factor Modulation:

• In the brain, LRP2 is critical for neurodevelopment, particularly during early stages of embryogenesis. It mediates signaling pathways associated with growth factors, such as sonic hedgehog (Shh) and bone morphogenetic protein (BMP), that guide neural tube development and brain morphogenesis.
• By binding these morphogens, LRP2 regulates their spatial distribution and bioavailability, impacting cellular differentiation and tissue patterning.

Vitamin and Hormone Transport:

• LRP2 transports essential vitamins and hormones, including vitamin A and D complexes. Its binding to retinol-binding protein (RBP) facilitates the uptake of vitamin A, which is critical for vision and cellular differentiation, while binding to vitamin D-binding protein helps maintain bone health through calcium regulation.
• Through these interactions, LRP2 contributes to the broader endocrine functions in the body, ensuring the systemic distribution and availability of these crucial nutrients.

Cellular Signaling and Morphogen Gradients:

• LRP2 modulates signaling pathways essential for organogenesis and cellular differentiation. For example, in early neural development, LRP2 controls sonic hedgehog (Shh) signaling by modulating its interaction with target cells, establishing morphogen gradients that influence tissue patterning and development.

Clinical Issues

Donnai-Barrow Syndrome:

• Mutations in LRP2 lead to Donnai-Barrow syndrome, a rare genetic disorder characterized by developmental abnormalities, including renal issues, vision impairment, and craniofacial deformities. This syndrome illustrates LRP2's role in development, as mutations disrupt ligand binding and endocytosis, affecting normal organ formation.

Chronic Kidney Disease:

• LRP2 dysfunction in the kidneys can lead to proteinuria, a condition marked by the excessive loss of protein in the urine. Since LRP2 is central to the reabsorption of filtered proteins, its impairment can exacerbate kidney damage, contributing to chronic kidney disease (CKD). LRP2 is being investigated as a therapeutic target for proteinuria and CKD management.

Vitamin Deficiency and Bone Health:

• LRP2 is essential for the uptake of vitamins such as A and D. Dysfunction in LRP2 can result in deficiencies that lead to bone-related health issues, including osteoporosis, due to impaired calcium absorption associated with vitamin D deficiency.

Neurodevelopmental Disorders:

• In the central nervous system, LRP2 is essential for embryonic brain development. Mutations affecting LRP2 expression or function can lead to neurological disorders due to impaired neurogenesis and brain patterning. Impaired LRP2 function has been linked to developmental delays and potential cognitive deficits, making it a focus of interest in neurodevelopmental research.

Summary

LRP2 (Low-Density Lipoprotein Receptor-Related Protein 2), also known as megalin, is a multifunctional endocytic receptor that plays critical roles in nutrient transport, hormone reabsorption, and cellular signaling. Structurally, LRP2 is a large glycoprotein comprising four primary ligand-binding domains, EGF-like repeats, β-propeller domains, and a cytoplasmic tail with motifs essential for clathrin-mediated endocytosis. This complex structure allows LRP2 to bind a wide array of ligands, including vitamin-binding proteins, hormones, and growth factors, which it internalizes for cellular functions.

Primarily expressed in the kidneys, brain, and inner ear, LRP2 is integral to organ-specific functions, such as nutrient reabsorption in the kidneys and neurodevelopment in the brain. Clinical conditions associated with LRP2 include Donnai-Barrow syndrome, chronic kidney disease, and neurodevelopmental disorders, each of which underscores its significance in normal organ function and development. Given its involvement in critical cellular processes, LRP2 is being investigated as a therapeutic target for various metabolic, developmental, and renal disorders.