LRP1

Low density lipoprotein receptor-related protein 1 (LRP1), also known as alpha-2-macroglobulin receptor (A2MR), apolipoprotein E receptor (APOER) or cluster of differentiation 91 (CD91), is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis. In humans, the LRP1 protein is encoded by the LRP1 gene. LRP1 is also a key signalling protein and, thus, involved in various biological processes, such as lipoprotein metabolism and cell motility, and diseases, such as neurodegenerative diseases, atherosclerosis, and cancer.

Structure

The LRP1 gene encodes a 600 kDa precursor protein that is processed by furin in the trans-Golgi complex, resulting in a 515 kDa alpha-chain and an 85 kDa beta-chain associated noncovalently. As a member of the LDLR family, LRP1 contains cysteine-rich complement-type repeats, EGF (gene) repeats, β-propeller domains, a transmembrane domain, and a cytoplasmic domain. The cytoplasmic domain of LRP1 is the alpha-chain, which comprises four ligand-binding domains (numbered I-IV) containing two, eight, ten, and eleven cysteine-rich complement-type repeats, respectively. These repeats bind extracellular matrix proteins, growth factors, proteases, protease inhibitor complexes, and other proteins involved in lipoprotein metabolism. Of the four domains, II and IV bind the majority of the protein’s ligands. The EGF repeats and β-propeller domains serve to release ligands in low pH conditions, such as inside endosomes, with the β-propeller postulated to displace the ligand at the ligand binding repeats. The transmembrane domain is the β-chain, which contains a 100-residue cytoplasmic tail. This tail contains two NPxY motifs that are responsible for the protein’s function in endocytosis and signal transduction.

Function

LRP1 is a member of the LDLR family and ubiquitously expressed in multiple tissues, though it is most abundant in vascular smooth muscle cells (SMCs), hepatocytes, and neurons. LRP1 plays a key role in intracellular signaling and endocytosis, which thus implicate it in many cellular and biological processes, including lipid and lipoprotein metabolism, protease degradation, platelet derived growth factor receptor regulation, integrin maturation and recycling, regulation of vascular tone, regulation of blood brain barrier permeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases such as neurodegenerative diseases, atherosclerosis, and cancer. To elaborate, LRP1 mainly contributes to regulation of protein activity by binding target proteins as a co-receptor, in conjunction with integral membrane proteins or adaptor proteins like uPA, to the lysosome for degradation. In lipoprotein metabolism, the interaction between LRP1 and APOE stimulates a signaling pathway that leads to elevated intracellular cAMP levels, increased protein kinase A activity, inhibited SMC migration, and ultimately, protection against vascular disease. While membrane-bound LRP1 performs endocytic clearance of proteases and inhibitors, proteolytic cleavage of its ectodomain allows the free LRP1 to compete with the membrane-bound form and prevent their clearance. Moreover, it is continuously endocytosed from the membrane and recycled back to the cell surface. Though the role of LRP1 in apoptosis is unclear, it is required for tPA to bind LRP1 in order to trigger the ERK1/2 signal cascade and promote cell survival.

Clinical significance

Alzheimer's disease

Neurons require cholesterol to function. Cholesterol is imported into the neuron by apolipoprotein E (apoE) via LRP1 receptors on the cell surface. It is thought that a causal factor in Alzheimer's is the malfunction of this process which damages neurons by starving them of cholesterol.

Over-accumulation of copper in the brain is associated with reduced LRP1 mediated clearance of amyloid beta across the blood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta that is thought to contribute to Alzheimer's disease.

Cardiovascular disease

Studies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease. Atherosclerosis is the primary cause of cardiovascular disease such as stroke and heart attacks. In the liver LRP1 is important for the removal of atherogenic lipoproteins (Chylomicron remnants, VLDL) and other proatherogenic ligands from the circulation. LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of the PDGFR-β in vascular smooth muscle cells. Finally, LRP1 in macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.

Cancer

LRP1 is involved in tumorigenesis, and is proposed to be a tumor suppressor. Notably, LRP1 functions in clearing proteases such as plasmin, urokinase-type plasminogen activator, and metalloproteinases, which contributes to prevention of cancer invasion, while its absence is linked to increased cancer invasion. However, the exact mechanisms require further study, as other studies have shown that LRP1 may also promote cancer invasion. One possible mechanism for the inhibitory function of LRP1 in cancer involves the LRP1-dependent endocytosis of 2′-hydroxycinnamaldehyde (HCA), resulting in decreased pepsin levels and, consequently, tumor progression. Alternatively, LRP1 may regulate focal adhesion disassembly of cancer cells through the ERK and JNK pathways to aid invasion. Moreover, LRP1 interacts with PAI-1 to recruit mast cells (MCs) and induce their degranulation, resulting in the release of MC mediators, activation of an inflammatory response, and development of glioma.

Interactions

LRP1 has been shown to interact with:

• A2-Macroglobulin,
• β-amyloid precursor protein,
• APBB1,
• APOE,
• Aprotinin,
• C1S/C1q inhibitor,
• CALR,
• CD44,
• Chylomicron,
• Circumsporozoite protein,
• Collectin,
• Complement C3,
• CTGF,
• DLG4,
• Elastase,
• Factor IXa,
• Factor VIIa,
• Fibronectin,
• Gentamicin,
• GIPC1,
• heparin cofactor II,
• Hepatic lipase,
• ITGB1BP1,
• Lactoferrin,
• Lipoprotein lipase,
• LPL,
• MAPK8IP1,
• MAPK8IP2,
• Midkine,
• MMP13,
• MMP2,
• MMP9,
• Neuroserpin,
• Nexin-1,
• NOS1AP,
• PAI 2,
• PAI-1,
• PDGF,
• tPA,
• uPA,
• Polymyxin B,
• Protein C inhibitor,
• Pseudomonas exotoxin A,
• RAP,
• Ricin A,
• SHC1, and
• Sphingolipid activator protein,
• SYNJ2BP.
• Tat,
• Thrombin,
• THBS1,
• Thrombospondin 2,
• TIMP1,
• TIMP2,
• TIMP3,
• Tissue factor pathway inhibitor,
• PLAT,
• Transforming growth factor-β,
• PLAUR,
• VLDL,

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles.

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|px|alt=Statin Pathway edit]]

File:StatinPathway_WP430.png

Statin Pathway edit

See also

• Cluster of differentiation
• Low density lipoprotein receptor gene family

External links

• CD91 Antigen at the US National Library of Medicine Medical Subject Headings (MeSH)