Studies of the Structure and Function of the LDL Receptor-related Protein (LRP) PDF Download
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Author: Robert Charles Kowal
Publisher:
ISBN:
Category :
Languages : en
Pages : 390
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Author: Robert Charles Kowal
Publisher:
ISBN:
Category :
Languages : en
Pages : 390
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Author:
Publisher: ScholarlyEditions
ISBN: 1464951012
Category : Science
Languages : en
Pages : 28
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Book Description
LDL Receptors: Advances in Research and Application: 2011 Edition is a ScholarlyPaper™ that delivers timely, authoritative, and intensively focused information about LDL Receptors in a compact format. The editors have built LDL Receptors: Advances in Research and Application: 2011 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about LDL Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of LDL Receptors: Advances in Research and Application: 2011 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
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Publisher: ScholarlyEditions
ISBN: 1481614037
Category : Science
Languages : en
Pages : 56
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Lipoprotein Receptors—Advances in Research and Application: 2012 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about Lipoprotein Receptors in a concise format. The editors have built Lipoprotein Receptors—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about Lipoprotein Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of Lipoprotein Receptors—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author:
Publisher: ScholarlyEditions
ISBN: 1481608711
Category : Science
Languages : en
Pages : 79
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Book Description
LDL Receptors—Advances in Research and Application: 2012 Edition is a ScholarlyBrief™ that delivers timely, authoritative, comprehensive, and specialized information about LDL Receptors in a concise format. The editors have built LDL Receptors—Advances in Research and Application: 2012 Edition on the vast information databases of ScholarlyNews.™ You can expect the information about LDL Receptors in this eBook to be deeper than what you can access anywhere else, as well as consistently reliable, authoritative, informed, and relevant. The content of LDL Receptors—Advances in Research and Application: 2012 Edition has been produced by the world’s leading scientists, engineers, analysts, research institutions, and companies. All of the content is from peer-reviewed sources, and all of it is written, assembled, and edited by the editors at ScholarlyEditions™ and available exclusively from us. You now have a source you can cite with authority, confidence, and credibility. More information is available at http://www.ScholarlyEditions.com/.
Author: Miklos Guttman
Publisher:
ISBN:
Category :
Languages : en
Pages : 184
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The LDLR family of receptors mediates the uptake of lipoprotein particles, and is essential for cholesterol homeostasis. The LDL receptor-related protein 1 (LRP-1) mediates internalization of a large number of diverse ligands and is widely implicated in Alzheimer's disease. Clusters of complement-type ligand binding repeats (CRs) in the LDL receptor family are thought to mediate the interactions between these receptors and their various ligands. Apolipoprotein E, a key ligand for cholesterol homeostasis, has been shown to interact with LDLR, LRP and VLDLR, through these clusters. LDLR and VLDLR each contain a single ligand-binding repeat cluster, whereas LRP contains three large clusters of ligand binding repeats, each with ligand binding functions. In order to study smaller units of these ligand binding clusters we have engineered a new approach to express and refold complement repeat (CR) domains in E. coli. This successfully produced high yields of refolded protein with the benefit of inexpensive isotope labeling for NMR studies. We have expressed a subdomain of sLRP3 (CR16-18) that has previously been shown to recapitulate ligand binding to the isolated receptor binding portion of ApoE (residues 130-149). Binding experiments with the ApoE recognition region of LDLR (LA3-5) and CR16-18 showed that each CR could interact with ApoE(130-149) and that a conserved W25/D30 pair within each repeat appears critical for high affinity. The triple repeat LA3-5 showed the expected interaction with the lipid complexed ApoE(1-191)*DMPC, but surprisingly CR16-18 did not interact with this form of ApoE. To understand these differences in ApoE binding affinity, we introduced mutations of conserved residues from LA5 into CR18, and produced a CR16-18 variant capable of binding ApoE(1-191)*DMPC. This change cannot fully be accounted for by the interaction with ApoE's proposed receptor binding region, therefore we speculate that LA5 is recognizing a distinct epitope on ApoE that may only exist in the lipid bound form. The combination of avidity effects with this distinct recognition process likely governs the ApoE-LDL receptor interaction. Since even the strongest interaction between ApoE(130-149) and a single repeat (CR17) was relatively weak, we constructed a CR17-ApoE(130-149) fusion protein to stabilize the interface for structural studies. The structure revealed a motif seen previously in all ligand CR interactions, in which lysine residues of the ligand interact with the calcium binding site of the CR. Like many ligands of CRs ApoE(130-149) binds as a helix, but with an unexpected turn at H140. These studies also revealed that little structural rearrangement occurs within CR17 upon binding. In addition, dynamics measurements of the free and bound CR17 reveal that certain regions become more ordered, while others become less ordered upon binding. The cytoplasmic tail of LRP, containing two NPXY motifs, has been implicated in the onset of Alzheimer's disease. To examine the intracellular interactions of LRP, as well as to separate which proteins bind to each NPXY motif and their phosphorylation dependence, each NPXY motif microdomain was prepared in both phosphorylated and non-phosphorylated forms and used to probe rodent brain extracts for binding proteins. Proteins that bound specifically to the microdomains were identified by LC-MS/MS, and confirmed by western blot. Recombinant proteins were then tested for binding to each NPXY motif. The NPXY450-- (membrane distal) was found to interact with a large number of proteins, many of which only bound the tyrosine-phosphorylated form. This microdomain also bound a significant number of other proteins in the unphosphorylated state. Many of the interactions were later confirmed to be direct with recombinant proteins. The NPXY44--3 (membrane proximal) bound many fewer proteins and only to the phosphorylated form.
Author: Johnny Eugene Croy
Publisher:
ISBN:
Category :
Languages : en
Pages : 390
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Author: Anothai Pocathikorn
Publisher:
ISBN:
Category : Lipoproteins
Languages : en
Pages : 302
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[Truncated abstract] The low density lipoprotein receptor-related protein (LRP), a member of the low-density lipoprotein (LDL) receptor gene family is involved in numerous biological processes including lipoprotein metabolism. This thesis concerns investigations into some aspects of LRP metabolism/regulation and possible roles in coronary artery disease (CAD). Specific aims were: to investigate the association between polymorphisms in the LRP gene and in its associated protein, the lipoprotein receptor-associated protein (RAP), with the risk of CAD; to extensively examine the influence of the LRP exon 22 C200T polymorphism on lipid metabolism; to develop and characterise assays for the mRNA expression of LRP and 2 other genes relevant to lipid metabolism, the LDL receptor (LDLR), and HMG CoA reductase (HMGCR); and finally, to apply the latter techniques to studies on the influence of genetic variation in LRP, and dietary and drug interventions, on LRP, LDLR and HMGCR mRNA expression in nucleated blood cells from healthy human subjects. Six hundred CAD subjects and 700 similarly aged controls were genotyped for 8 LRP gene polymorphisms as well as for the RAP V311M polymorphism. ... In the final phase of my studies, I examined the influence of 4 weeks therapy with a cholesterol lowering drug, an HMGCR inhibitor, atorvastatin (20mg daily), on the mRNA expression of LDLR, LRP and HMGCR in human nucleated blood cells. Twelve normal Caucasian male subjects aged 49 ± 5 (SD) years were studied. Plasma total cholesterol and LDL-C decreased by averages of 29 % and 41 % after the 4 week period. This was accompanied by an elevation in LDLR mRNA expression by approximately 30 35 %. In contrast, there was no significant effect on LRP and HMGCR mRNA expression. In conclusion, the original findings in this thesis included: demonstration of a strong influence of the LRP exon 22 C200T polymorphism on coronary artery disease and LDLR expression, but without a clear effect on fasting or postprandial lipid levels; data on the biological variation in LDLR and LRP gene expression in nucleated blood cells from normal subjects; the influence of an oral fat load on the expression viii of these genes, finding that LDLR was significantly depressed; and finally, the observation that statin therapy upregulated LDLR in nucleated blood cells.
Author: André Gauthier
Publisher:
ISBN:
Category : Cholesterol
Languages : en
Pages : 344
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Author: Rita Kohen Avramoglu
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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Book Description
The low density lipoprotein receptor-related protein (LRP) is a 600 kDa endocytic plasma membrane receptor. LRP is involved in the uptake of numerous structurally and functionally unrelated ligands, including alpha2-macroglobulin:protease complexes (alpha2M*), apolipoprotein E-enriched remnant lipoproteins, Pseudomonas exotoxin A (PEA), and receptor associated protein (RAP). To date, analysis of LRP ligand-binding regions has proven challenging due to its large size and repeating modular structure. Using a recombinant DNA approach, full-length somatic chicken LRP, as well as several deletion mutants, were stably expressed in a mutant CHO-derived cell line deficient in endogenous LRP expression. LRP100, LRP67 and LRP25 encode 100%, 67% and 25% of the protein respectively, with LRP67 and LRP25 encoding large internal deletions but retaining an N-terminal portion, transmembrane region, and cytoplasmic tail. These three mutants were found to possess varying degrees of ligand-binding activity toward alpha 2M*, RAP, and PEA. Generation of this expression system has allowed the mapping of several LRP ligands to the N-terminal portion of the receptor and should allow further study of domains within LRP responsible for its multifunctionality. It was recently postulated that eight spacer regions within LRP containing repeating YWTD motifs adopt beta-propeller conformations. While developing cell, lines expressing refined mutants encoding deletions of putative ligand-binding regions, disruption of the naturally occurring, ordered arrangement of beta-propeller domains was found to have an effect on intracellular trafficking and plasma membrane presentation of mutant receptors. Although highly expressed, several mutants possessing crippled beta-propellers were not detected at the plasma membrane by biotin labeling. These mutants also exhibited delayed or no resistance to endoglycosidase H (endo H) suggesting ER exit was delayed or impaired. Restoration of integral beta-propellers and flanking EGF modules restored ER exit and plasma membrane presentation to a transport incompetent mutant. The beta-propeller domains may play an important role in conferring structural stability to LRP. Caution should therefore be exercised in the mutagenesis of this enormous receptor.
Author: Yoshiharu Takayama
Publisher: Springer Science & Business Media
ISBN: 9400724675
Category : Medical
Languages : en
Pages : 118
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Lactoferrin is an iron-binding glycoprotein belonging to the transferrin family. It acts as a defense in host animals against microbes and viruses, since it has a broad spectrum of antimicrobial and antiviral activities. Lactoferrin has been shown to regulate the growth and differentiation of many types of cells. The results of recent studies indicate that lactoferrin is a potent regulator of dermal fibroblasts, and promotes cutaneous wound healing. The collagen gel contraction, a model of wound contraction during wound healing process, and migration of human fibroblasts were enhanced by lactoferrin. LRP-1 (LDL Receptor related Protein-1) acts as a signaling receptor for lactoferrin that mediate fibroblast response to lactoferrin by activating ERK/MAPK signaling pathway. In addition, lactoferrin promotes biosynthesis of extracellular matrix (ECM) component such as type-I collagen and hyaluronan. Hyaluronan is a major component of ECM in connective tissue and promotes wound healing. The promoting effect of lactoferrin on hyaluronan production was accompanied by promotion of HAS2 (hyaluronan synthase 2) expression. These observations suggest that lactoferrin promotes the wound healing by providing an ECM that promotes fibroblast migration. Lactoferrin is also known for its anti-inflammatory and immune modulating properties. According to recent in vivo study, lactoferrin promotes wound repair by promoting the early inflammatory phase of wound healing. Based on this, recombinant human lactoferrin was subsequently tested clinically in a Phase II trial in patients with diabetic ulcers and was found to be effective. Lactoferrin should be further evaluated in patients with diabetic and other types of ulcers.
