TheLRP1 gene encodes a 600 kDaprecursor protein that is processed byfurin in the trans-Golgi complex, resulting in a 515 kDa alpha-chain and an 85 kDa beta-chain associated noncovalently.[8][10][11] As a member of theLDLR family, LRP1 contains cysteine-rich complement-type repeats,EGF (gene) repeats, β-propeller domains, atransmembrane domain, and acytoplasmic domain.[9] The extracellular domain of LRP1 is the alpha-chain, which comprises fourligand-binding domains (numbered I-IV) containing two, eight, ten, and eleven cysteine-rich complement-type repeats, respectively.[8][9][10][11] These repeats bindextracellular matrix proteins,growth factors,proteases,protease inhibitorcomplexes, and other proteins involved inlipoproteinmetabolism.[8][9] Of the four domains, II and IV bind the majority of the protein's ligands.[11] The EGF repeats and β-propeller domains serve to releaseligands in lowpH conditions, such as insideendosomes, with the β-propeller postulated to displace the ligand at the ligand binding repeats.[9] The transmembrane domain is the β-chain, which contains a 100-residuecytoplasmic tail. This tail contains two NPxY motifs that are responsible for the protein's function inendocytosis andsignal transduction.[8]
LRP1 is a member of the LDLR family and ubiquitously expressed in multipletissues, though it is most abundant invascularsmooth muscle cells (SMCs),hepatocytes, andneurons.[8][9] LRP1 plays a key role in intracellular signaling and endocytosis, which implicates it in many cellular and biological processes, includinglipid andlipoproteinmetabolism,proteasedegradation,platelet derived growth factor receptor regulation,integrin maturation and recycling, regulation of vascular tone, regulation ofblood brain barrierpermeability,cell growth,cell migration,inflammation, andapoptosis, as well asdiseases such as neurodegenerative diseases, atherosclerosis, and cancer.[7][8][9][10][11] To elaborate, LRP1 mainly contributes to regulate protein activity by binding target proteins as aco-receptor, in conjunction withintegral membrane proteins or adaptor proteins likeuPA, to thelysosome for degradation.[9][10][11] In lipoprotein metabolism, the interaction between LRP1 andAPOE stimulates a signaling pathway that leads to elevated intracellularcAMP levels, increasedprotein kinase A activity, inhibited SMC migration, and ultimately, protection againstvascular disease.[9]Whilemembrane-bound LRP1 performs endocytic clearance of proteases and inhibitors,proteolytic cleavage of itsectodomain allows the free LRP1 to compete with the membrane-bound form and prevent their clearance.[8] Several sheddases have been implicated in the proteolytic cleavage of LRP1 such as ADAM10,[12] ADAM12,[13] ADAM17[14] and MT1-MMP.[13] LRP1 is also continuously endocytosed from the membrane and recycled back to the cell surface.[9] 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.[15]
Neurons requirecholesterol to function. Cholesterol is imported into the neuron by apolipoprotein E (apoE) via LRP1 receptors on the cell surface. It has been theorized that a causal factor inAlzheimer's is the decrease of LRP1 mediated by the metabolism of the amyloid precursor protein, leading to decreased neuronal cholesterol and increased amyloid beta.[16]
LRP1 is also implicated in the effective clearance of Aβ from the brain to the periphery across theblood-brain barrier.[17][18] LRP1 mediates pathways that interact with astrocytes and pericytes, which are associated with the blood-brain barrier. In support of this, LRP1 expression is reduced in endothelial cells as a result of normal aging and Alzheimer's disease in humans and animal models of the disease.[19][20] This clearance mechanism is modulated by theapoE isoforms, with the presence of the apoE4 isoform resulting in reduced transcytosis of Aβ in in vitro models of the blood-brain barrier.[21] The reduced clearance appears to be, at least in part, as a result of an increase in the ectodomain shedding of LRP1 by sheddases, resulting in the formation of soluble LRP1 which is no longer able to transcytose the Aβ peptides.[22]
In addition, over-accumulation ofcopper in the brain is associated with reduced LRP1 mediated clearance ofamyloid beta across theblood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta thatis thought to contribute to Alzheimer's disease.[23]
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 atherogeniclipoproteins (Chylomicron remnants, VLDL) and other proatherogenic ligands from the circulation.[24][25] LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of thePDGFR-β in vascularsmooth muscle cells.[26][27] Finally, LRP1 inmacrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[28][29]
LRP1 is involved in tumorigenesis, and is proposed to be a tumor suppressor. Notably, LRP1 functions in clearing proteases such asplasmin,urokinase-type plasminogen activator, andmetalloproteinases, which contributes to prevention ofcancer 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 decreasedpepsin levels and, consequently, tumor progression.[9] Alternatively, LRP1 may regulatefocal adhesion disassembly of cancer cells through theERK andJNK pathways to aid invasion.[8] Moreover, LRP1 interacts withPAI-1 to recruitmast cells (MCs) and induce theirdegranulation, resulting in the release of MC mediators, activation of an inflammatory response, and development ofglioma.[10]
^Myklebost O, Arheden K, Rogne S, Geurts van Kessel A, Mandahl N, Herz J, et al. (Jul 1989). "The gene for the human putative apoE receptor is on chromosome 12 in the segment q13-14".Genomics.5 (1):65–9.doi:10.1016/0888-7543(89)90087-6.PMID2548950.
^abcdeKang HS, Kim J, Lee HJ, Kwon BM, Lee DK, Hong SH (Aug 2014). "LRP1-dependent pepsin clearance induced by 2'-hydroxycinnamaldehyde attenuates breast cancer cell invasion".The International Journal of Biochemistry & Cell Biology.53:15–23.doi:10.1016/j.biocel.2014.04.021.PMID24796846.
^Bachmeier C, Paris D, Beaulieu-Abdelahad D, Mouzon B, Mullan M, Crawford F (2013-01-01). "A multifaceted role for apoE in the clearance of beta-amyloid across the blood-brain barrier".Neuro-Degenerative Diseases.11 (1):13–21.doi:10.1159/000337231.PMID22572854.S2CID30189180.
Li Z, Dai J, Zheng H, Liu B, Caudill M (Mar 2002). "An integrated view of the roles and mechanisms of heat shock protein gp96-peptide complex in eliciting immune response".Frontiers in Bioscience.7 (4): d731–51.doi:10.2741/A808.PMID11861214.
van der Geer P (May 2002). "Phosphorylation of LRP1: regulation of transport and signal transduction".Trends in Cardiovascular Medicine.12 (4):160–5.doi:10.1016/S1050-1738(02)00154-8.PMID12069755.
1cr8: LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN COMPLEMENT REPEAT 8
1d2l: NMR SOLUTION STRUCTURE OF COMPLEMENT-LIKE REPEAT CR3 FROM THE LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN (LRP). EVIDENCE FOR SPECIFIC BINDING TO THE RECEPTOR BINDING DOMAIN OF HUMAN ALPHA-2 MACROGLOBULIN
1j8e: Crystal structure of ligand-binding repeat CR7 from LRP
2fyj: NMR Solution structure of calcium-loaded LRP double module
2fyl: Haddock model of the complex between double module of LRP, CR56, and first domain of receptor associated protein, RAP-d1.
