LRP1 - LDL receptor related protein 1 |Elisa - Clia - Antibody - Protein

Background

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) is a multifunctional cell surface receptor with diverse roles in cellular processes, including endocytosis, lipid transport, signal transduction, and the regulation of inflammation. Part of the low-density lipoprotein (LDL) receptor family, LRP1 has high sequence homology with the LDL receptor but a much broader set of ligands, facilitating interactions with various proteins, such as apolipoprotein E (ApoE), tissue plasminogen activator (tPA), and matrix metalloproteinases. LRP1 is highly expressed in the liver, brain, and adipose tissues, where it plays crucial roles in metabolism, neuroprotection, and vascular health.

In neurons, LRP1 mediates neuroprotective processes and is implicated in the clearance of amyloid-beta, a key protein in Alzheimer’s disease pathology. In addition to metabolic and neural roles, LRP1 impacts cellular migration and adhesion, contributing to processes related to tissue injury repair, cancer metastasis, and inflammatory diseases. Its function and widespread expression make LRP1 a focal point in therapeutic research for conditions including neurodegenerative diseases, atherosclerosis, and certain cancers.

Protein Structure

LRP1 is a large, multi-domain glycoprotein with an approximate molecular weight of 600 kDa, consisting of over 4,500 amino acids. Its structure is integral to its function as a receptor capable of interacting with a wide range of ligands and cellular proteins. LRP1 is synthesized as a single polypeptide chain that undergoes proteolytic cleavage to form two subunits, which remain associated via non-covalent interactions.

Heavy Chain (515 kDa):

• The extracellular, or heavy chain, of LRP1 contains four ligand-binding domains (termed I-IV), each capable of binding different ligands. Each domain consists of cysteine-rich repeats that are characteristic of LDL receptor family proteins, enhancing ligand binding through calcium-dependent interactions.
• The ligand-binding domains exhibit specificity and selectivity for various ligands. For example, Domain II binds α2-macroglobulin, while Domain IV binds both ApoE and tissue plasminogen activator (tPA).
• The heavy chain contains multiple EGF-like (epidermal growth factor) domains and complement-type repeats that contribute to protein-protein interactions. These domains allow for interaction with extracellular proteins that modulate its activity, such as matrix metalloproteinases (MMPs), which are essential in extracellular matrix remodeling.

Light Chain (85 kDa):

• The light chain of LRP1 is a transmembrane protein that anchors the heavy chain to the cell membrane and extends into the cytoplasm. It consists of a short extracellular stalk region, a single-pass transmembrane domain, and a long cytoplasmic tail.
• The cytoplasmic tail is critical for signaling and endocytosis functions, containing two NXPY (Asn-Pro-X-Tyr) motifs essential for clathrin-mediated endocytosis and signal transduction.
• These motifs interact with adaptor proteins such as disabled-2 (Dab2) and phosphotyrosine-binding proteins, which mediate the internalization of LRP1-ligand complexes and relay signals to intracellular pathways.

Proteolytic Processing and Shedding:

• LRP1 is synthesized as a precursor protein that undergoes cleavage by a furin protease, separating the heavy and light chains. Additionally, a process known as “shedding” can release the extracellular portion of LRP1 from the cell surface in response to cellular stress, altering cellular interactions and signaling dynamics.

Classification and Subtypes

LRP1 belongs to the low-density lipoprotein receptor (LDLR) family. The family includes other receptors such as LRP2 (megalin), LDLR, and VLDLR, each having unique ligand-binding properties. However, LRP1 has no subtypes and exists as a single receptor with specific domain configurations and functions.

Function and Biological Significance

LRP1 is involved in various physiological and pathophysiological processes:

Endocytosis and Ligand Clearance:

• LRP1 mediates the endocytosis and clearance of numerous ligands, including ApoE, α2-macroglobulin, and tissue plasminogen activator (tPA). The receptor’s ability to internalize these ligands regulates lipid transport, protein degradation, and metabolic waste clearance.
• In the central nervous system, LRP1 plays a role in the clearance of amyloid-beta peptides, a function implicated in Alzheimer’s disease prevention, as efficient amyloid-beta clearance prevents plaque formation and neurotoxicity.

Regulation of Inflammation:

• LRP1 modulates inflammatory responses by controlling the activity of cytokines and proteases involved in inflammation. By binding and internalizing molecules such as matrix metalloproteinases (MMPs), LRP1 aids in the regulation of tissue remodeling and inflammatory signaling.
• LRP1 interactions with inflammatory mediators also affect the NF-κB signaling pathway, leading to downstream effects that influence immune cell recruitment and cytokine production.

Neuroprotection and Neural Function:

• In the brain, LRP1 is crucial for neuron survival, synaptic plasticity, and memory formation. It influences signaling pathways, such as ERK and Akt, which are necessary for cell survival and neuroprotection.
• In Alzheimer’s disease, LRP1’s role in amyloid-beta clearance is particularly significant, and LRP1 dysfunction has been linked to amyloid accumulation, a hallmark of the disease.

Role in Lipid Transport:

• LRP1 is involved in lipid transport by binding and internalizing lipoprotein particles containing ApoE. This process regulates lipid homeostasis and contributes to the distribution of cholesterol and other lipids, impacting conditions such as atherosclerosis.

Tumorigenesis and Cancer Metastasis:

• LRP1 has both pro- and anti-tumorigenic roles depending on the tissue and cancer type. By regulating extracellular protease levels, such as MMPs, LRP1 influences tumor cell migration and invasion. In some cancers, LRP1 promotes metastasis by facilitating the breakdown of extracellular barriers, while in others, it restricts tumor growth through interactions with specific signaling pathways.

Clinical Issues

Alzheimer’s Disease:

• In Alzheimer’s disease, LRP1’s role in amyloid-beta clearance is crucial. Reduced expression or dysfunction of LRP1 in neurons is associated with impaired amyloid-beta clearance, leading to its accumulation and plaque formation, which are neurotoxic and contribute to cognitive decline. LRP1-targeted therapies are under investigation to enhance amyloid-beta clearance and reduce neuroinflammation.

Atherosclerosis:

• LRP1 expression in vascular smooth muscle cells and macrophages regulates lipid uptake and inflammation in the vascular system. Dysfunctional LRP1 has been implicated in the progression of atherosclerosis by increasing lipid deposition and inflammation within arterial walls. Reduced LRP1 expression in vascular cells is associated with increased susceptibility to atherosclerosis and cardiovascular disease.

Cancer:

• LRP1 influences cancer progression, primarily through its regulation of extracellular matrix degradation and cell migration. In certain cancers, high LRP1 expression is correlated with increased invasion and metastasis, while in others, it may inhibit growth through apoptotic pathways. As a result, LRP1 is considered both a potential biomarker and therapeutic target, depending on the cancer type and stage.

Liver and Metabolic Diseases:

• Since LRP1 is highly expressed in the liver, it is involved in lipid metabolism and clearance of hepatic lipoproteins. Dysregulation of LRP1 in liver cells can lead to lipid accumulation, which contributes to conditions such as non-alcoholic fatty liver disease (NAFLD) and insulin resistance.

Fibrosis:

• LRP1 expression in fibroblasts modulates extracellular matrix composition and turnover. Through its effects on protease regulation, LRP1 influences fibrosis in tissues such as the lung, liver, and kidney, where excessive extracellular matrix deposition leads to organ dysfunction.

Summary

LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) is a large, multifunctional cell surface receptor with extensive roles in endocytosis, lipid metabolism, inflammation, neuroprotection, and tumor progression. Structurally, it comprises a large extracellular heavy chain with four ligand-binding domains and a transmembrane light chain with a cytoplasmic tail essential for signaling and internalization. Through its interactions with a broad range of ligands, LRP1 mediates essential cellular processes, impacting various physiological and pathological states.

In neurobiology, LRP1 is particularly significant for amyloid-beta clearance, making it a critical factor in Alzheimer’s disease research. In vascular health, it regulates lipid metabolism and inflammation, influencing atherosclerosis progression. LRP1’s dual role in cancer, either as a facilitator or inhibitor of metastasis, highlights its complexity and importance as a biomarker and therapeutic target. Its broad functional capabilities make LRP1 relevant in metabolic, neurological, and cancer-related disorders, underscoring its therapeutic potential across multiple clinical fields.