Lrp1

The LRP1 gene encodes a precursor protein with a molecular weight of 600 kDa, which, under the action of an intracellular protease, furin breaks down in the trans-section of the Golgi apparatus into two chains: 515 kDa alpha chain (extracellular protein) and 85 kDa beta chain ( cytoplasmic protein), which remain associated with each other by non-covalent bonds ^{[4] [6] [7]} . Like all proteins of the low density lipoprotein receptor family, LRP1 contains cysteine-rich complementary-type repeats, EGF repeats, beta-propeller domain, and cytoplasmic domain ^[5] . The large extracellular domain of LRP1α, or the alpha chain, contains ligand-binding domains numbered from I to IV, which include 2, 8, 10 and 11 cysteine ​​repeats, respectively ^{[4] [5] [6] [7]} . These repeats bind extracellular matrix proteins, growth factors, proteases, protease inhibitor complexes, and other lipoprotein metabolism proteins ^{[4] [5]} . Of the 4 ligand-binding domains, domains II and IV are responsible for the binding of most LRP1 ligands. ^[7] EGF repeats and β-propeller domains provide the release of ligands with decreasing pH occurring in the endosomes , while the β-propeller shifts the released ligand ^[5] . The transmembrane domain (LRP1β), or β-chain of a protein, contains 100 amino acids of the cytoplasmic C-terminus. The cytoplasmic motif NPxY plays a role in endocytosis and signal transmission . ^[four]

The LRP1 protein is expressed in almost all tissues. The highest receptor level is found in smooth muscle cells, hepatocytes and neurons ^{[4] [5]} . LRP1 plays a role in intracellular signaling and endocytosis, which are involved in many biological processes: lipid and lipoprotein metabolism, degradation of proteases, regulation of platelet growth factor receptor , maturation and recycling of integrins , regulation of vascular tone, regulation of permeability of the blood-brain barrier , cell migration, inflammation and apoptosis . It also plays a role in the development of neurodegenerative diseases, atherosclerosis and cancer ^{[3] [4] [5] [6] [7]} .

Basically, LRP1 is involved in the regulation of protein activity by binding the ligand as a co-receptor together with transmembrane or adapter proteins such as plasmin , followed by ligand degradation in lysosomes ^{[5] [6] [7]} . In lipoprotein metabolism, LRP1 binds apolipoprotein E , which stimulates the signaling pathway, which causes an increase in the level of intracellular cAMP , increases the activity of protein kinase A and inhibits the smooth muscle cell migration. In general, this leads to protection against vascular diseases ^[5] . While membrane-bound LRP1 provides purification from proteases and inhibitors, proteolytic cleavage of the ectodomain releases LRP1, which, on the contrary, competes with membrane LRP1, which leads to a delay in normal protein function ^[4] . Several sheddases are involved in the cleavage of the extracellular domain of LRP1, including ADAM10 , ^[8] ADAM12 , ^[9] ADAM17 ^[10] and MT1-MMP . ^[9] . LRP1 is constantly endocytosed from the membrane and again recycled to the cell membrane ^[5] .

Although the role of LRP1 in apoptosis is less studied, it is known that this requires the binding of LRP1 to tPA , which leads to the ERK1 / 2 signaling cascade and leads to increased cell survival ^[11] .

Alzheimer's Disease

The normal functioning of neurons requires cholesterol . Cholesterol is delivered to neurons by apoE- containing lipoproteins that bind to LRP1 receptors expressed on neurons. It is suggested that one of the causes of Alzheimer's disease may be a decrease in LRP1 mediated by APP metabolism, which ultimately leads to a decrease in neuronal cholesterol and an increase in amyloid beta (Aβ) ^[12] .

LRP1 also plays a role in the effective clearance of Aβ from the brain through the blood-brain barrier ^{[13] [14]} . It is known that the expression of LRP1 decreases in endothelial cells during aging in both humans and animals ^{[15] [16]} . The clearance mechanism is modulated by the apoE polymorphism, and the presence of the apoE4 isoform leads to reduced Aβ transcytosis in the blood-brain barrier models ^[17] . In addition, a decreased clearance of Aβ can occur due to increased cleavage of the ectodomain of LRP1 by sheddases, which also slows down the clearance of Aβ ^[18] .

Cardiovascular Disease

LRP1 plays a role in several processes associated with the development of cardiovascular disease. Atherosclerosis is the main cause of cardiovascular diseases such as stroke and myocardial infarction . In the liver, LRP1 plays an important role in removing atherogenic lipoproteins, such as chylomicron remnants and VLDL, and other proatherogenic components from the bloodstream ^{[19] [20]} . LRP1 also plays a cholesterol-dependent role in atherosclerosis by modulating the activity and cell localization of PDGFR-β in smooth muscle cells ^{[21] [22]} . Finally, macrophage LRP1 modulates the extracellular matrix and inflammatory response, which is important in the progression of atherosclerosis ^{[23] [24]} .

• Low Density Lipoprotein Receptor Family