LRP1 explained

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.[1] [2] [3] 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.[4] [5]

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.[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 inhibitor complexes, and other proteins involved in lipoprotein metabolism.[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-residue cytoplasmic 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 vascular smooth muscle cells (SMCs), hepatocytes, and neurons.[4] [5] LRP1 plays a key role in intracellular signaling and endocytosis, which implicates 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.[3] [4] [5] [6] [7] To elaborate, LRP1 mainly contributes to regulate 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. LRP1 is also continuously 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] 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.[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]

Interactions

LRP1 has been shown to interact with:

Interactive pathway map

See also

Further reading

Notes and References

  1. Herz J, Hamann U, Rogne S, Myklebost O, Gausepohl H, Stanley KK . Surface location and high affinity for calcium of a 500-kd liver membrane protein closely related to the LDL-receptor suggest a physiological role as lipoprotein receptor . The EMBO Journal . 7 . 13 . 4119–27 . Dec 1988 . 3266596 . 455121 . 10.1002/j.1460-2075.1988.tb03306.x.
  2. Myklebost O, Arheden K, Rogne S, Geurts van Kessel A, Mandahl N, Herz J, Stanley K, Heim S, Mitelman F . The gene for the human putative apoE receptor is on chromosome 12 in the segment q13-14 . Genomics . 5 . 1 . 65–9 . Jul 1989 . 2548950 . 10.1016/0888-7543(89)90087-6 .
  3. Web site: Entrez Gene: LRP1 low density lipoprotein receptor-related protein 1.
  4. Etique N, Verzeaux L, Dedieu S, Emonard H . LRP-1: a checkpoint for the extracellular matrix proteolysis . BioMed Research International . 2013 . 152163 . 2013 . 23936774 . 10.1155/2013/152163 . 3723059. free .
  5. Lillis AP, Mikhailenko I, Strickland DK . Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability . Journal of Thrombosis and Haemostasis . 3 . 8 . 1884–93 . Aug 2005 . 16102056 . 10.1111/j.1538-7836.2005.01371.x . 20991690 . free .
  6. Roy A, Coum A, Marinescu VD, Põlajeva J, Smits A, Nelander S, Uhrbom L, Westermark B, Forsberg-Nilsson K, Pontén F, Tchougounova E . Glioma-derived plasminogen activator inhibitor-1 (PAI-1) regulates the recruitment of LRP1 positive mast cells . Oncotarget . Jun 2015 . 26164207 . 6 . 27 . 23647–61 . 10.18632/oncotarget.4640 . 4695142.
  7. Kang HS, Kim J, Lee HJ, Kwon BM, Lee DK, Hong SH . LRP1-dependent pepsin clearance induced by 2'-hydroxycinnamaldehyde attenuates breast cancer cell invasion . The International Journal of Biochemistry & Cell Biology . 53 . 15–23 . Aug 2014 . 24796846 . 10.1016/j.biocel.2014.04.021 .
  8. Shackleton. B.. Crawford. F.. Bachmeier. C.. 2016-08-08. Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1 ectodomain shedding. Fluids and Barriers of the CNS. 13. 1. 14. 10.1186/s12987-016-0038-x. 2045-8118. 4977753. 27503326 . free .
  9. Selvais. Charlotte. D'Auria. Ludovic. Tyteca. Donatienne. Perrot. Gwenn. Lemoine. Pascale. Troeberg. Linda. Dedieu. Stéphane. Noël. Agnès. Nagase. Hideaki. 2017-03-31. Cell cholesterol modulates metalloproteinase-dependent shedding of low-density lipoprotein receptor-related protein-1 (LRP-1) and clearance function. The FASEB Journal. 25. 8. 2770–2781. 10.1096/fj.10-169508. free . 0892-6638. 3470721. 21518850.
  10. Liu. Qiang. Zhang. Juan. Tran. Hien. Verbeek. Marcel M.. Reiss. Karina. Estus. Steven. Bu. Guojun. 2009-04-16. LRP1 shedding in human brain: roles of ADAM10 and ADAM17. Molecular Neurodegeneration. 4. 17. 10.1186/1750-1326-4-17. 1750-1326. 2672942. 19371428 . free .
  11. Hu K, Lin L, Tan X, Yang J, Bu G, Mars WM, Liu Y . tPA protects renal interstitial fibroblasts and myofibroblasts from apoptosis . Journal of the American Society of Nephrology . 19 . 3 . 503–14 . Mar 2008 . 18199803 . 10.1681/ASN.2007030300 . 2391054.
  12. Liu Q, Zerbinatti CV, Zhang J, Hoe HS, Wang B, Cole SL, Herz J, Muglia L, Bu G . Amyloid precursor protein regulates brain apolipoprotein E and cholesterol metabolism through lipoprotein receptor LRP1 . Neuron . 56 . 1 . 66–78 . Oct 2007 . 17920016 . 2045076 . 10.1016/j.neuron.2007.08.008 .
  13. Deane. R. Bell. RD. Sagare. A. Zlokovic. BV. 2017-03-31. Clearance of amyloid-β peptide across the blood-brain barrier: Implication for therapies in Alzheimer's disease. CNS & Neurological Disorders Drug Targets. 8. 1. 16–30. 1871-5273. 2872930. 19275634. 10.2174/187152709787601867.
  14. Storck. Steffen E.. Meister. Sabrina. Nahrath. Julius. Meißner. Julius N.. Schubert. Nils. Spiezio. Alessandro Di. Baches. Sandra. Vandenbroucke. Roosmarijn E.. Bouter. Yvonne. 2016-01-04. Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier. The Journal of Clinical Investigation. en. 126. 1. 10.1172/JCI81108. 0021-9738. 4701557. 26619118. 123–136.
  15. Kang. D. E.. Pietrzik. C. U.. Baum. L.. Chevallier. N.. Merriam. D. E.. Kounnas. M. Z.. Wagner. S. L.. Troncoso. J. C.. Kawas. C. H.. 2000-11-01. Modulation of amyloid beta-protein clearance and Alzheimer's disease susceptibility by the LDL receptor-related protein pathway. The Journal of Clinical Investigation. 106. 9. 1159–1166. 10.1172/JCI11013. 0021-9738. 301422. 11067868.
  16. Shibata. M.. Yamada. S.. Kumar. S. R.. Calero. M.. Bading. J.. Frangione. B.. Holtzman. D. M.. Miller. C. A.. Strickland. D. K.. 2000-12-01. Clearance of Alzheimer's amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. The Journal of Clinical Investigation. 106. 12. 1489–1499. 10.1172/JCI10498. 0021-9738. 387254. 11120756.
  17. 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. 10.1159/000337231. 1660-2862. 22572854. 30189180.
  18. Bachmeier. Corbin. Shackleton. Ben. Ojo. Joseph. Paris. Daniel. Mullan. Michael. Crawford. Fiona. 2017-03-31. Apolipoprotein E isoform-specific effects on lipoprotein receptor processing. Neuromolecular Medicine. 16. 4. 686–696. 10.1007/s12017-014-8318-6. 1535-1084. 4280344. 25015123.
  19. Singh I, Sagare AP, Coma M, Perlmutter D, Gelein R, Bell RD, Deane RJ, Zhong E, Parisi M, Ciszewski J, Kasper RT, Deane R . Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance . Proceedings of the National Academy of Sciences of the United States of America . 110 . 36 . 14771–6 . Sep 2013 . 23959870 . 3767519 . 10.1073/pnas.1302212110 . 2013PNAS..11014771S . free .
  20. Gordts PL, Reekmans S, Lauwers A, Van Dongen A, Verbeek L, Roebroek AJ . 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 . Sep 2009 . 19667105 . 10.1161/ATVBAHA.109.192211 . free .
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