LRP1

Official Full Name

LDL receptor related protein 1

Organism

Homo sapiens

Gene ID

4035

Background

This gene encodes a member of the low-density lipoprotein receptor family of proteins. The encoded preproprotein is proteolytically processed by furin to generate 515 kDa and 85 kDa subunits that form the mature receptor (PMID: 8546712). This receptor is involved in several cellular processes, including intracellular signaling, lipid homeostasis, and clearance of apoptotic cells. In addition, the encoded protein is necessary for the alpha 2-macroglobulin-mediated clearance of secreted amyloid precursor protein and beta-amyloid, the main component of amyloid plaques found in Alzheimer patients. Expression of this gene decreases with age and has been found to be lower than controls in brain tissue from Alzheimer's disease patients. [provided by RefSeq, Oct 2015]

Synonyms

APR; KPA; LRP; A2MR; CD91; DDH3; APOER; LRP1A; TGFBR5; IGFBP3R; IGFBP-3R; IGFBP3R1

Cat.No.	Product Name	Price
CSC-DC001001	Panoply™ Human ARVCF Knockdown Stable Cell Line	Inquiry
CSC-DC001851	Panoply™ Human C1D Knockdown Stable Cell Line	Inquiry
CSC-DC008852	Panoply™ Human LRP1 Knockdown Stable Cell Line	Inquiry
CSC-SC001001	Panoply™ Human ARVCF Over-expressing Stable Cell Line	Inquiry
CSC-SC001851	Panoply™ Human C1D Over-expressing Stable Cell Line	Inquiry
CSC-SC008852	Panoply™ Human LRP1 Over-expressing Stable Cell Line	Inquiry
CSC-RT1764	C1D Knockout Cell Line-HeLa	Inquiry
CLOE-0806	Human LRP1 HEK293 Cell Lysate	Inquiry
CLKO-1610	C1D KO Cell Lysate-HeLa	Inquiry

Cat.No.	Product Name	Price
AD01401Z	Human Arvcf adenoviral particles	Inquiry
LV05553L	human ARVCF (NM_001670) lentivirus particles	Inquiry
LV06919L	human C1D (NM_006333) lentivirus particles	Inquiry
LV17314L	human LRP1 (NM_002332) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH241018	shRNA set against Mouse Arvcf (NM_033474.2)	Inquiry
SHW005738	shRNA set against Chicken LRP1 (NM_205242)	Inquiry
SHG075305	shRNA set against Mouse Arvcf(NM_033474.2)	Inquiry
SHG118711	shRNA set against Mouse C1d(NM_020558.3)	Inquiry
SHH160967	shRNA set against Human LRP1(NM_002332.2)	Inquiry
SHH160985	shRNA set against Mouse Lrp1(NM_008512.2)	Inquiry
SHH241014	shRNA set against Human Arvcf (NM_001670.2)	Inquiry
SHH250274	shRNA set against Mouse C1D (NM_020558.3)	Inquiry
SHH250278	shRNA set against Rat C1D (NM_001106021.1)	Inquiry
SHH333947	shRNA set against Human LRP1 (NM_002332.2)	Inquiry
SHH333951	shRNA set against Mouse LRP1 (NM_008512.2)	Inquiry
SHW001658	shRNA set against Chicken C1D (NM_001031036)	Inquiry
SHW003461	shRNA set against Chicken C1D (NM_001244737)	Inquiry
SHW004978	shRNA set against Chicken ARVCF (NM_204465)	Inquiry
SHW007515	shRNA set against Danio rerio C1D (NM_001007059)	Inquiry

Cat.No.	Product Name	Price
MiUTR3H-08888	C1D miRNA 3'UTR clone	Inquiry
MiUTR3H-04830	ARVCF miRNA 3'UTR clone	Inquiry
MiUTR1M-06743	LRP1 miRNA 3'UTR clone	Inquiry
CDCB167213	Chicken LRP1 ORF Clone (NM_205242)	Inquiry
MiUTR1M-02349	C1D miRNA 3'UTR clone	Inquiry
MiUTR1M-01721	ARVCF miRNA 3'UTR clone	Inquiry
MiUTR1H-05896	LRP1 miRNA 3'UTR clone	Inquiry
CDFR009395	Rat Arvcf cDNA Clone(NM_001131013.1)	Inquiry
CDFR005795	Rat C1d cDNA Clone(NM_001106021.1)	Inquiry
MiUTR3H-08887	C1D miRNA 3'UTR clone	Inquiry
CDCS410749	Human LRP1 ORF Clone (BC045107)	Inquiry
CDCS409195	Human C1D ORF Clone (BC005235)	Inquiry
CDCS409194	Human C1D ORF Clone (BC009584)	Inquiry
CDCR376830	Rat Arvcf ORF Clone(NM_001131013.1)	Inquiry
CDCR280891	Human ARVCF ORF Clone(NM_001670.2)	Inquiry
CDCR030622	Mouse Arvcf ORF clone (NM_033474.2)	Inquiry
CDCL186418	Human TGF-beta 3 ORF clone(NM_003239.2)	Inquiry
CDCL185194	Human LRP1 ORF clone(NM_002332.2)	Inquiry
CDCH388042	Rat LRP1 ORF clone(NM_001130490.1)	Inquiry
CDCH388041	Mouse LRP1 ORF clone(NM_008512.2)	Inquiry
CDCB195474	Rabbit LRP1 ORF clone (XM_002720944.3)	Inquiry
CDCB194787	Rabbit C1D ORF clone (XM_008254321.1)	Inquiry
CDCB185598	Rabbit ARVCF ORF clone (XM_008250594.1)	Inquiry
CDCB168990	Danio rerio C1D ORF Clone (NM_001007059)	Inquiry
CDCB166453	Chicken ARVCF ORF Clone (NM_204465)	Inquiry
CDCB164936	Chicken C1D ORF Clone (NM_001244737)	Inquiry
CDCR372823	Rat C1d ORF Clone(NM_001106021.1)	Inquiry
CDCB163133	Chicken C1D ORF Clone (NM_001031036)	Inquiry

Detailed Information

Low-density lipoprotein receptor-related protein 1 (LRP1) was first discovered in 1988 through screening mouse lymphocyte and human liver cDNA libraries for sequences homologous to the apoE binding domain of the LDL receptor (LDLR). Compared to LDLR, LRP1 is a structurally massive type I transmembrane protein, encoding 4,525 amino acids and consisting of two subunits: a 515 kDa N-terminal extracellular subunit and an 85 kDa C-terminal transmembrane subunit, which are associated non-covalently. These two subunits are transported to the cell surface after being cleaved by furin enzyme in the trans-Golgi network.

Figure 1: Domain structure schematic of LRP1 and LDLR showing ligand binding domains, cysteine-rich repeats, furin cleavage site, β-propeller domain, and endocytic motifs (NPXY, YXXL) in the cytoplasmic tail. Figure 1. Schematic diagram of domain structure for LRP1 and LDLR. (Shinohara M, et al., 2017)

The extracellular region of LRP1 contains four cysteine-rich ligand-binding domains (I-IV), comprising 2, 8, 10, and 11 complement-type repeats, respectively. Domains II and IV are the primary binding sites for most ligands in the presence of calcium ions. Additionally, its cytoplasmic tail contains multiple NPXY motifs, which are critical signals for mediating endocytosis through clathrin-coated pits, and work in concert with adjacent YXXL and dileucine motifs to achieve rapid internalization. The EGF-like repeats and YWTD β-propeller domains in the extracellular region facilitate the dissociation of ligands in endocytic vesicles.

Effective transport of LRP1 to the cell surface depends on a 39 kDa molecular chaperone—Receptor-Associated Protein (RAP). RAP binds to LRP1 in the early secretory pathway, preventing premature binding with other ligands, and dissociates in the late, low pH environment. RAP, as a universal ligand for LRP1, can block the binding of almost all known LRP1 ligands.

To date, over 40 proteins have been identified as LRP1 ligands, including Aβ, apoE, and activated α2-macroglobulin. However, controversy exists regarding whether Aβ directly binds to domains II and IV of LRP1. While Deane et al. demonstrated in vitro that Aβ (particularly the monomeric form of Aβ40) can bind to these domains, Yamada et al. were unable to reproduce these results in similar experiments. Some studies suggest that LRP1 might depend on other Aβ-binding proteins (such as heparan sulfate proteoglycans) to jointly mediate Aβ internalization. The aggregated or oligomeric forms of Aβ have relatively weaker affinity for LRP1.

Notably, apoE's ability to bind to LRP1 is significantly influenced by its conformation and lipidation state.

Beyond ligand metabolism, LRP1 can also regulate cellular signaling pathways by forming complexes with membrane proteins such as platelet-derived growth factor receptor (PDGF) and N-methyl-D-aspartate receptor (NMDA receptor). Furthermore, LRP1 can be cleaved by β-secretase or α-secretase and γ-secretase, producing intracellular fragments that can act as transcriptional regulatory factors, modulating the expression of multiple genes including interferon-γ, with functions similar to amyloid precursor protein (APP). Simultaneously, the soluble form of LRP1 (sLRP1) also plays an important role in Aβ metabolism.

LRP1 is highly expressed in various tissues, including the liver, brain, and vascular system. Conventional LRP1 knockout mice exhibit early embryonic lethality, in stark contrast to the non-lethal phenotype of LDLR knockout mice. Animal experiments with conditional knockout in hepatocytes, macrophages, adipocytes, and vascular smooth muscle cells indicate that LRP1, by regulating ligand metabolism and signaling pathway intensity, is crucial for tissue development and homeostasis maintenance. Its dysfunction may be associated with diseases such as atherosclerosis and cancer.

Particularly in the nervous system, LRP1 is highly relevant to the pathogenesis of Alzheimer's disease. Animal studies suggest that LRP1 regulates Aβ metabolism and brain homeostasis through multiple pathways, which may depend on apoE subtypes or be independent of apoE. However, since most studies are based on cell or animal models, its specific role in AD remains uncertain. Future research needs to systematically examine: first, changes in LRP1 expression and function at different stages (especially preclinical) in human AD patients; second, the diverse functional roles LRP1 might play in different cell types, ages, disease stages, and apoE subtype backgrounds. These studies will help develop LRP1-targeted therapeutic strategies for AD.

References

Shinohara M, Tachibana M, Kanekiyo T, et al. Role of LRP1 in the pathogenesis of Alzheimer's disease: evidence from clinical and preclinical studies. J Lipid Res. 2017 Jul;58(7):1267-1281.
Jaeger S, Pietrzik CU. Functional role of lipoprotein receptors in Alzheimer's disease. Curr Alzheimer Res. 2008 Feb;5(1):15-25.

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