Low density lipoprotein receptor-related protein 1(LRP1), also known asAlpha -2-macroglobulin receptor(A2MR),apolipoprotein E receptor(APOER) orcluster of differentiation 91(CD91), is aproteinforming areceptorfound in theplasma membraneofcellsinvolved in receptor-mediatedendocytosis.In humans, the LRP1 protein is encoded by theLRP1gene.[5][6][7]LRP1 is also a keysignallingprotein and, thus, involved in various biological processes, such aslipoproteinmetabolismandcell motility,anddiseases,such asneurodegenerative diseases,atherosclerosis,andcancer.[8][9]
Structure
editTheLRP1gene encodes a 600 kDaprecursor proteinthat is processed byfurinin 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 theLDLRfamily, LRP1 contains cysteine-rich complement-type repeats,EGF (gene)repeats, β-propeller domains, atransmembranedomain, and acytoplasmicdomain.[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 matrixproteins,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 releaseligandsin lowpHconditions, 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-residuecytoplasmictail. This tail contains two NPxY motifs that are responsible for the protein's function inendocytosisandsignal transduction.[8]
Function
editLRP1 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, includinglipidandlipoproteinmetabolism,proteasedegradation,platelet derived growth factor receptorregulation,integrinmaturation and recycling, regulation of vascular tone, regulation ofblood brain barrierpermeability,cell growth,cell migration,inflammation,andapoptosis,as well asdiseasessuch 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 proteinsor adaptor proteins likeuPA,to thelysosomefor degradation.[9][10][11]In lipoprotein metabolism, the interaction between LRP1 andAPOEstimulates a signaling pathway that leads to elevated intracellularcAMPlevels, increasedprotein kinase Aactivity, inhibited SMC migration, and ultimately, protection againstvascular disease.[9] Whilemembrane-boundLRP1 performs endocytic clearance of proteases and inhibitors,proteolytic cleavageof itsectodomainallows 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]
Clinical significance
editAlzheimer's disease
editNeuronsrequirecholesterolto 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'sis 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 theapoEisoforms, 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 ofcopperin the brain is associated with reduced LRP1 mediated clearance ofamyloid betaacross theblood brain barrier.This defective clearance may contribute to the buildup of neurotoxic amyloid-beta thatis thought to contributeto Alzheimer's disease.[23]
Cardiovascular disease
editStudies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease.Atherosclerosisis 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-βin vascularsmooth muscle cells.[26][27]Finally, LRP1 inmacrophageshas an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[28][29]
Cancer
editLRP1 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 decreasedpepsinlevels and, consequently, tumor progression.[9]Alternatively, LRP1 may regulatefocal adhesiondisassembly of cancer cells through theERKandJNKpathways to aid invasion.[8]Moreover, LRP1 interacts withPAI-1to recruitmast cells(MCs) and induce theirdegranulation,resulting in the release of MC mediators, activation of an inflammatory response, and development ofglioma.[10]
Interactions
editLRP1 has been shown tointeractwith:
- A2-Macroglobulin,[9]
- β-amyloid precursor protein,[9]
- APBB1,[30]
- APOE,[9][31][32]
- Aprotinin,[9]
- C1S/C1qinhibitor,[9]
- CALR,[9][33]
- CD44,[8]
- Chylomicron,[9]
- Circumsporozoite protein,[9]
- Collectin,[9]
- Complement C3,[9]
- CTGF,[9]
- DLG4,[34]
- Elastase,[9]
- Factor IXa,[9]
- Factor VIIa,[9]
- Fibronectin,[9]
- Gentamicin,[9]
- GIPC1,[34]
- Heat shock proteins:gp96,hsp70,hsp90,[35]
- heparin cofactor II,[9]
- Hepatic lipase,[9]
- ITGB1BP1,[34]
- Lactoferrin,[9]
- Lipoprotein lipase,[9]
- LPL,[36][37][38]
- MAPK8IP1,[34]
- MAPK8IP2,[34]
- Midkine,[9]
- MMP13,[8][9]
- MMP2,[8]
- MMP9,[8][9]
- Neuroserpin,[9]
- Nexin-1,[9]
- NOS1AP,[34]
- PAI 2,[8]
- PAI-1,[8][10]
- PDGF,[9]
- tPA,[8][9]
- uPA,[8][9]
- Polymyxin B,[9]
- Protein C inhibitor,[9]
- Pseudomonas exotoxinA,[9]
- RAP,[9]
- RicinA,[9]
- SHC1,[39][40]and
- Sphingolipid activator protein,[9]
- SYNJ2BP.[34]
- Tat,[9]
- Thrombin,[9]
- THBS1,[9][41][42][43]
- Thrombospondin 2,[9]
- TIMP1,[8]
- TIMP2,[8]
- TIMP3,[8]
- Tissue factor pathway inhibitor,[9]
- PLAT,[44][45]
- Transforming growth factor-β,[9]
- PLAUR,[46]
- VLDL,[9]
Interactive pathway map
editClick on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ^The interactive pathway map can be edited at WikiPathways:"Statin_Pathway_WP430".
See also
editReferences
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Further reading
edit- 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.
- May P, Herz J (May 2003)."LDL receptor-related proteins in neurodevelopment".Traffic.4(5): 291–301.doi:10.1034/j.1600-0854.2003.00086_4_5.x.PMID12713657.S2CID23565545.
- 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.S2CID83711249.
- 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.S2CID20991690.
External links
edit- CD91+Antigenat the U.S. National Library of MedicineMedical Subject Headings(MeSH)