LRP1
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| Location (UCSC) | Chr 12: 57.13 – 57.21 Mb | Chr 10: 127.37 – 127.46 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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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
Structure
The LRP1 gene encodes a 600 kDa
complexes, and other proteins involved in lipoprotein metabolism.[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 release ligands in low pH conditions, such as inside endosomes, 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-residue cytoplasmic tail. This tail contains two NPxY motifs that are responsible for the protein's function in endocytosis and signal transduction.[8]
Function
LRP1 is a member of the LDLR family and ubiquitously expressed in multiple
blood brain barrier permeability, cell growth, cell migration, inflammation, and apoptosis, as well as diseases 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 a co-receptor, in conjunction with integral membrane proteins or adaptor proteins like uPA, to the lysosome for degradation.[9][10][11] 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.[9]
While proteolytic cleavage of its ectodomain 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]
Clinical significance
Alzheimer's disease
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.[16]
LRP1 is also implicated in the effective clearance of Aβ from the brain to the periphery across the blood-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 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.[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 of
blood brain barrier. This defective clearance may contribute to the buildup of neurotoxic amyloid-beta that is thought to contribute to Alzheimer's disease.[23]
Cardiovascular disease
Studies have elucidated different roles for LRP1 in cellular processes relevant for cardiovascular disease.
macrophages has an effect on atherosclerosis through the modulation of the extracellular matrix and inflammatory responses.[28][29]
Cancer
LRP1 is involved in tumorigenesis, and is proposed to be a tumor suppressor. Notably, LRP1 functions in clearing proteases such as
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.[10]
Interactions
LRP1 has been shown to
interact
with:
- A2-Macroglobulin,[9]
- amyloid precursor protein,[9]
- APBB1,[30]
- APOE,[9][31][32]
- Aprotinin,[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]
- heparin cofactor II,[9]
- Hepatic lipase,[9]
- ITGB1BP1,[34]
- Lactoferrin,[9]
- Lipoprotein lipase,[9]
- LPL,[36][37][38]
- MAPK8IP1,[34]
- MAPK8IP2,[34]
- Midkine,[9]
- MMP2,[8]
- MMP9,[8][9]
- Neuroserpin,[9]
- Nexin-1,[9]
- NOS1AP,[34]
- PAI 2,[8]
- PDGF,[9]
- tPA,[8][9]
- uPA,[8][9]
- Polymyxin B,[9]
- Protein C inhibitor,[9]
- Pseudomonas exotoxin A,[9]
- RAP,[9]
- Ricin A,[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]
- Transforming growth factor-β,[9]
- PLAUR,[46]
- VLDL,[9]
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
Statin pathway edit
- ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
See also
- Cluster of differentiation
- Low density lipoprotein receptor gene family
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000123384 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040249 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 3266596.
- PMID 2548950.
- ^ a b "Entrez Gene: LRP1 low density lipoprotein receptor-related protein 1".
- ^ PMID 23936774.
- ^ S2CID 20991690.
- ^ PMID 26164207.
- ^ PMID 24796846.
- PMID 27503326.
- ^ PMID 21518850.
- PMID 19371428.
- PMID 18199803.
- PMID 17920016.
- PMID 19275634.
- PMID 26619118.
- PMID 11067868.
- PMID 11120756.
- S2CID 30189180.
- PMID 25015123.
- PMID 23959870.
- PMID 19667105.
- PMID 9449704.
- S2CID 2070128.
- PMID 17505534.
- PMID 21730304.
- PMID 17303763.
- PMID 9837937.
- PMID 277965.
- PMID 2762297.
- PMID 12821648.
- ^ PMID 10827173.
- PMID 11290339.
- PMID 7510694.
- PMID 7989348.
- PMID 1281473.
- PMID 12789267.
- PMID 11854294.
- S2CID 12198474.
- PMID 9045712.
- PMID 7775583.
- PMID 10632583.
- PMID 1502153.
- PMID 11359936.
Further reading
- 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. PMID 11861214.
- van der Geer P (May 2002). "Phosphorylation of LRP1: regulation of transport and signal transduction". Trends in Cardiovascular Medicine. 12 (4): 160–5. PMID 12069755.
- May P, Herz J (May 2003). "LDL receptor-related proteins in neurodevelopment". Traffic. 4 (5): 291–301. S2CID 23565545.
- 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. PMID 15705932.
- Huang SS, Huang JS (Oct 2005). "TGF-beta control of cell proliferation". Journal of Cellular Biochemistry. 96 (3): 447–62. S2CID 83711249.
- 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. S2CID 20991690.
External links
- CD91+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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Lipids: lipoprotein particle metabolism | ||
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| Lipoprotein particle classes and subclasses |
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| Apolipoproteins | ||
| Extracellular enzymes | ||
| Lipid transfer proteins | ||
| Cell surface receptors | ||
ATP-binding cassette transporter | ||