LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation

Kounnas, Maria Z.; Moir, Robert D.; Rebeck, G. William; Bush, Ashley I.; Argraves, W. Scott; Tanzi, Rudolph E.; Hyman, Bradley T.; Strickland, Dudley K.

doi:10.1016/0092-8674(95)90320-8

Cited by 471 publications

(327 citation statements)

References 64 publications

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“…Indeed, several apoE receptors interact with APP and modulate its trafficking and processing. LRP1 interacts with APP extracellularly by binding to the Kunitz-type protease inhibitor (KPI) domain that is present in the longer forms of APP (APP751 and APP770) (Kounnas et al 1995). Further studies showed that LRP1 also interacts with the neuronal isoform of APP lacking the KPI domain (APP695).…”

Section: Lrp1: Effects On App Ab and Apoe Metabolism Regulation Of mentioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

661

602

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Section: Lrp1: Effects On App Ab and Apoe Metabolism Regulation Of mentioning

confidence: 99%

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Holtzman

Herz²,

2012

Cold Spring Harbor Perspectives in Medicine

661

602

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“…LRP is also believed to mediate the differential neurite outgrowth responses of cultured neurons in response to the various isoforms of ApoE (Gliemann 1998;Sun et al 1998). APP has also been shown to stimulate neurite outgrowth, however, LRP may not be directly involved in this response, at least in cultures of chick sympathetic neurons (Kounnas et al 1995;Qiu et al 1995;Postuma et al 1998). Thus, lipoproteins and their receptors may play several roles in brain development and function.…”

Section: Role Of Lipoprotein Receptors In the Brainmentioning

confidence: 99%

“…Inheritance of the apoE4 allele is a risk factor for late-onset Alzheimer's disease (Rubinsztein 1997). Another ligand of LRP is the secreted form of APP (Kounnas et al 1995). ApoE, APP, and LRP have been found in senile plaques and polymorphisms in LRP have been linked to Alzheimer's disease Hollenbach et al 1998).…”

Section: Role Of Lipoprotein Receptors In the Brainmentioning

confidence: 99%

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

Rice¹,

Curran²

1999

Genes & Development

141

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“…A 39-kDa protein, termed the receptor-associated protein (RAP) (17), binds to several members of the LDL receptor family (18 -20) and blocks their ligand binding capacity. LRP mediates the cellular uptake and subsequent degradation of proteinases, such as tissue-type plasminogen activator (21) and urinary-type plasminogen activator (22), proteinase-inhibitor complexes, such as ␣ 2 -macroglobulin-proteinase complexes (23,24), soluble amyloid precursor protein (25), and apolipoprotein E-enriched lipoproteins (26,27). LRP is expressed in many tissues, and is a major endocytic receptor in the liver and in the central nervous system (for reviews, see Refs.…”

mentioning

confidence: 99%

Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)

Mikhailenko

Krylov²,

Argraves

et al. 1997

Journal of Biological Chemistry

106

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Thrombospondin-1 (TSP-1) is a large modular trimeric protein that has been proposed to play a diverse role in biological processes. Newly synthesized TSP-1 either is incorporated into the matrix or binds to the cell surface where it is rapidly internalized and degraded. TSP-1 catabolism is mediated by the low density lipoprotein receptor-related protein (LRP), a large endocytic receptor that is a member of the low density lipoprotein receptor family. Using adenovirus-mediated gene transfer experiments, we demonstrate that the very low density lipoprotein receptor can also bind and internalize TSP-1. An objective of the current investigation was to identify the portion of TSP-1 that binds to these endocytic receptors. The current studies found that the amino-terminal heparin binding domain (HBD, residues 1-214) of mouse TSP-1, when prepared as a fusion protein with glutathione S-transferase (GST), bound to purified LRP with an apparent K D ranging from 10 to 25 nM. Recombinant HBD (rHBD) purified following proteolytic cleavage of GST-HBD, also bound to purified LRP, but with an apparent K D of 830 nM. The difference in affinity was attributed to the fact that GST-HBD exists in solution as a dimer, whereas rHBD is a monomer. Like TSP-1, 125 I-labeled GST-HBD or 125 I-labeled rHBD were internalized and degraded by wild type fibroblasts that express LRP, but not by fibroblasts that are genetically deficient in LRP. The catabolism of both 125 I-labeled GST-HBD and rHBD in wild type fibroblast was blocked by the 39-kDa receptor-associated protein, an inhibitor of LRP function. GST-HBD and rHBD both completely blocked catabolism of 125 I-labeled TSP-1 in a dose-dependent manner, as did antibodies prepared against the HBD. Taken together, these data provide compelling evidence that the amino-terminal domain of TSP-1 binds to LRP and thus the recognition determinants on TSP-1 for both LRP and for cell surface proteoglycans reside within the same TSP-1 domain. Further, high affinity binding of TSP-1 to LRP likely results from the trimeric structure of TSP-1.Thrombospondin-1 (TSP-1) 1 is a large glycoprotein composed of three identical subunits, which are covalently linked by interchain disulfide bonds. This molecule is a part of a family of proteins that currently consists of five members (for reviews, see Refs. 1-3). Each subunit of TSP-1 is composed of an aminoterminal heparin binding domain, a type I procollagen homology region, three properdin repeats, three epidermal growth factor-like repeats, seven calcium binding repeats, and a carboxyl-terminal domain (4). TSP-1 has been proposed to play a diverse role in numerous biological processes; these include embryonic development (5), angiogenesis (6), and hemostasis (7,8). The ability of TSP-1 to influence these biological processes has been attributed to its capacity to bind to matrix proteins, proteinases, growth factors, and cell surface receptors.Given that TSP-1 appears to influence a large number of biological processes, it is not surprising that levels of TSP-1 ar...

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LDL receptor-related protein, a multifunctional ApoE receptor, binds secreted β-amyloid precursor protein and mediates its degradation

Cited by 471 publications

References 64 publications

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

Cellular Internalization and Degradation of Thrombospondin-1 Is Mediated by the Amino-terminal Heparin Binding Domain (HBD)

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