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.[4][6][7] 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.[5] The extracellular 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.[4][5][6][7] These repeats bind extracellular matrix proteins, growth factors, proteases, protease inhibitorcomplexes, and other proteins involved in lipoproteinmetabolism.[4][5] Of the four domains, II and IV bind the majority of the protein’s ligands.[7] 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.[5] 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 in endocytosis and signal transduction.[4]
Function
LRP1 is a member of the LDLR family and ubiquitously expressed in multiple tissues, though it is most abundant in vascularsmooth muscle cells (SMCs), hepatocytes, and neurons.[4][5] LRP1 plays a key role in intracellular signaling and endocytosis, which thus implicate it in many cellular and biological processes, including lipid and lipoproteinmetabolism, proteasedegradation, platelet derived growth factor receptor regulation, integrin maturation and recycling, regulation of vascular tone, regulation of blood brain barrierpermeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases such as neurodegenerative diseases, atherosclerosis, and cancer.[3][4][5][6][7] 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.[5][6][7] 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.[5]
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.[4] Several sheddases have been implicated in the proteolytic cleavage of LRP1 such as ADAM10,[8] ADAM12,[9] ADAM17[10] and MT1-MMP.[9] LRP1 is alsocontinuously endocytosed from the membrane and recycled back to the cell surface.[5] 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.[11]
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 has been theorized that a causal factor in Alzheimer's is the decrease of LRP1 mediated by the metabolism of the amyloid precursor protein, leading to decreased neuronal cholesterol and increased amyloid beta.[12]
LRP1 is also implicated in the effective clearance of Aβ from the brain to the periphery across the blood-brain barrier.[13][14] 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.[15][16] This clearance mechanism is modulated by the apoE isoforms, with the presence of the apoE4 isoform resulting in reduced transcytosis of Aβ in in vitro models of the blood-brain barrier.[17] 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.[18]
In addition, 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.[19]
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.[20][21] LRP1 has a cholesterol-independent role in atherosclerosis by modulating the activity and cellular localization of the PDGFR-β in vascular smooth muscle cells.[22][23] Finally, LRP1 in macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[24][25]
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.[5] Alternatively, LRP1 may regulate focal adhesion disassembly of cancer cells through the ERK and JNK pathways to aid invasion.[4] 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.[6]
↑Myklebost O, Arheden K, Rogne S, Geurts van Kessel A, Mandahl N, Herz J, Stanley K, Heim S, Mitelman F (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.
↑ 7.07.17.27.37.4Kang 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, Corbin; Paris, Daniel; Beaulieu-Abdelahad, David; Mouzon, Benoit; Mullan, Michael; Crawford, Fiona (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. ISSN1660-2862. PMID22572854.
↑Gordts PL, Reekmans S, Lauwers A, Van Dongen A, Verbeek L, Roebroek AJ (Sep 2009). "Inactivation of the LRP1 intracellular NPxYxxL motif in LDLR-deficient mice enhances postprandial dyslipidemia and atherosclerosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 29 (9): 1258–64. doi:10.1161/ATVBAHA.109.192211. PMID19667105.
↑Overton CD, Yancey PG, Major AS, Linton MF, Fazio S (Mar 2007). "Deletion of macrophage LDL receptor-related protein increases atherogenesis in the mouse". Circulation Research. 100 (5): 670–7. doi:10.1161/01.RES.0000260204.40510.aa. PMID17303763.
↑Trommsdorff M, Borg JP, Margolis B, Herz J (Dec 1998). "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". The Journal of Biological Chemistry. 273 (50): 33556–60. doi:10.1074/jbc.273.50.33556. PMID9837937.
↑Poswa M (Mar 1977). "[Team growth by acquiring an apprentice]". Quintessenz Journal. 7 (3): 21–3. PMID277965.
↑ 30.030.130.230.330.430.530.6Gotthardt M, Trommsdorff M, Nevitt MF, Shelton J, Richardson JA, Stockinger W, Nimpf J, Herz J (Aug 2000). "Interactions of the low density lipoprotein receptor gene family with cytosolic adaptor and scaffold proteins suggest diverse biological functions in cellular communication and signal transduction". The Journal of Biological Chemistry. 275 (33): 25616–24. doi:10.1074/jbc.M000955200. PMID10827173.
↑Basu S, Binder RJ, Ramalingam T, Srivastava PK (Mar 2001). "CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin". Immunity. 14 (3): 303–13. doi:10.1016/s1074-7613(01)00111-x. PMID11290339.
↑Williams SE, Inoue I, Tran H, Fry GL, Pladet MW, Iverius PH, Lalouel JM, Chappell DA, Strickland DK (Mar 1994). "The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP". The Journal of Biological Chemistry. 269 (12): 8653–8. PMID7510694.
↑Nykjaer A, Nielsen M, Lookene A, Meyer N, Røigaard H, Etzerodt M, Beisiegel U, Olivecrona G, Gliemann J (Dec 1994). "A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor-related protein and inhibits lipase-mediated uptake of lipoprotein in cells". The Journal of Biological Chemistry. 269 (50): 31747–55. PMID7989348.
↑Chappell DA, Fry GL, Waknitz MA, Iverius PH, Williams SE, Strickland DK (Dec 1992). "The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase". The Journal of Biological Chemistry. 267 (36): 25764–7. PMID1281473.
↑Barnes H, Ackermann EJ, van der Geer P (Jun 2003). "v-Src induces Shc binding to tyrosine 63 in the cytoplasmic domain of the LDL receptor-related protein 1". Oncogene. 22 (23): 3589–97. doi:10.1038/sj.onc.1206504. PMID12789267.
↑Loukinova E, Ranganathan S, Kuznetsov S, Gorlatova N, Migliorini MM, Loukinov D, Ulery PG, Mikhailenko I, Lawrence DA, Strickland DK (May 2002). "Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP). Evidence for integrated co-receptor function between LRP and the PDGF". The Journal of Biological Chemistry. 277 (18): 15499–506. doi:10.1074/jbc.M200427200. PMID11854294.
↑Wang S, Herndon ME, Ranganathan S, Godyna S, Lawler J, Argraves WS, Liau G (Mar 2004). "Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans". Journal of Cellular Biochemistry. 91 (4): 766–76. doi:10.1002/jcb.10781. PMID14991768.
↑Mikhailenko I, Krylov D, Argraves KM, Roberts DD, Liau G, Strickland DK (Mar 1997). "Cellular internalization and degradation of thrombospondin-1 is mediated by the amino-terminal heparin binding domain (HBD). High affinity interaction of dimeric HBD with the low density lipoprotein receptor-related protein". The Journal of Biological Chemistry. 272 (10): 6784–91. doi:10.1074/jbc.272.10.6784. PMID9045712.
↑Zhuo M, Holtzman DM, Li Y, Osaka H, DeMaro J, Jacquin M, Bu G (Jan 2000). "Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation". The Journal of Neuroscience. 20 (2): 542–9. PMID10632583.
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: 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.
Llorente-Cortés V, Badimon L (Mar 2005). "LDL receptor-related protein and the vascular wall: implications for atherothrombosis". Arteriosclerosis, Thrombosis, and Vascular Biology. 25 (3): 497–504. doi:10.1161/01.ATV.0000154280.62072.fd. PMID15705932.
Huang SS, Huang JS (Oct 2005). "TGF-beta control of cell proliferation". Journal of Cellular Biochemistry. 96 (3): 447–62. doi:10.1002/jcb.20558. PMID16088940.
Lillis AP, Mikhailenko I, Strickland DK (Aug 2005). "Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability". Journal of Thrombosis and Haemostasis. 3 (8): 1884–93. doi:10.1111/j.1538-7836.2005.01371.x. PMID16102056.
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