scholarly journals The Spacing between Cysteines Two and Three of the LDL-A Module of Tva Is Important for Subgroup A Avian Sarcoma and Leukosis Virus Entry

2004 ◽  
Vol 78 (2) ◽  
pp. 683-691 ◽  
Author(s):  
Tia Rai ◽  
Deborah Marble ◽  
Kayla Rihani ◽  
Lijun Rong
Keyword(s):  
Viral Entry ◽  
Critical Role ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Chimeric Protein ◽  
Amino Terminus ◽  
Viral Glycoprotein ◽  
Interaction Domain ◽  
Avian Sarcoma

ABSTRACT Rong et al. have demonstrated previously that with a few substitutions, the fourth repeat of human low-density lipoprotein (hLDL-A4) receptor can functionally replace the LDL-A module of Tva, the cellular receptor for subgroup A avian sarcoma and leukosis virus (ASLV-A), in viral entry (L. Rong, K. Gendron, and P. Bates, Proc. Natl. Acad. Sci. USA 95:8467-8472, 1998). Here we have shown that swapping the amino terminus of hLDL repeat 5 (hLDL-A5) with that of Tva, in addition to the corresponding substitutions made in human LDL-A4, was required to convert hLDL-A5 into an efficient ASLV-A receptor. These results substantiated our previous findings regarding the role of the specific residues in the viral interaction domain of Tva and demonstrated the critical role of the amino terminus of the Tva LDL-A module in ASLV-A infection. Furthermore, we have shown that the residues between cysteines 2 and 3 of the Tva LDL-A module in a Tva/LDL-A5 chimeric protein can be functionally replaced by the corresponding region of another LDL-A module, human LDL receptor-related protein repeat 22 (LDL-A22), to mediate efficient ASLV-A entry. Since the only conserved feature between the C2-C3 region of LDL-A22 and the Tva LDL-A module is that both contain nine amino acids of which none are conserved, we conclude that the spacing between C2 and C3 of the LDL-A module of Tva is an important determinant for ASLV-A entry. Thus, the present study provides strong evidence to support our hypothesis that one role of the N terminus of the LDL-A module of Tva is to allow proper folding and conformation of the protein for optimal interaction with the viral glycoprotein EnvA in ASLV-A entry.

The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

scholarly journals The role of cyclooxygenase-2 on endurance exercise training in female LDL-receptor knockout ovariectomized mice

2013 ◽  
Vol 85 (3) ◽  
pp. 1157-1164 ◽  
Author(s):  
FLAVIA DE OLIVEIRA ◽  
LAURA B.M. MAIFRINO ◽  
GUSTAVO P.P. DE JESUS ◽  
JULIANA G. CARVALHO ◽  
CLAUDIA MARCHON ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Exercise Training ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Cyclooxygenase 2 ◽  
Sedentary Control ◽  
Down Regulation ◽  
Ovariectomized Mice ◽  
Cox 2

Estrogen deprivation in postmenopausal women increases cardiovascular risk. Cardiovascular risk as a result of atherosclerosis is able to induce an inflammatory disease as far as cyclooxygenase-2 ( COX-2) expression. The purpose of the study was to investigate the role of COX-2 on exercise training in female mice low-density lipoprotein receptor knockout ( LDL-KO) with or without ovariectomy. A total of 15 female C57BL/6 mice and 15 female LDL-KO mice were distributed into 6 groups: sedentary control, sedentary control ovariectomized, trained control ovariectomized, LDL-KO sedentary, LDL-KO sedentary ovariectomized and LDL-KO trained ovariectomized. The ascending part of the aorta was stained with H&E and COX-2 expression was assessed by immunohistochemistry. Results revealed that ovariectomy as well as exercise training were not able to induce histopathological changes in mouse aorta for all groups investigated. LDL-KO mice demonstrated plaque containing cholesterol clefts, foamy histiocytes and mild inflammatory process for all groups indistinctly. Ovariectomy induced a strong immunoexpression in atherosclerosis lesion of LDL-KO mice. Nevertheless, a down-regulation of COX-2 expression was detected in LDL-KO trained ovariectomized when compared to LDL-KO sedentary. Our results are consistent with the notion that exercise training is able to modulate COX-2 expression in LDL-KO mice as a result of COX-2 down-regulation.

scholarly journals Oxidized LDL but not angiotensin II induces the interaction between LOX-1 and AT1 receptors

2020 ◽  
Author(s):  
Li Lin ◽  
Ning Zhou ◽  
Le Kang ◽  
Qi Wang ◽  
Jian Wu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Oxidized Low Density Lipoprotein ◽  
Protein Activation

Oxidized low-density lipoprotein (Ox-LDL) can induce cardiac hypertrophy, but the mechanism is still unclear. Here we elucidate the role of angiotensin II (AngII) receptor (AT1-R) in Ox-LDL-induced cardiomycyte hypertrophy. Inhibition of Ox-LDL receptor LOX-1 and AT1-R rather than AngII abolished Ox-LDL-induced hypertrophic responses. Similar results were obtained from the heart of mice lacking endogenous Ang II and their cardiomyocytes. Ox-LDL but not AngII induced binding of LOX-1 to AT1-R, and the inhibition of LOX-1 or AT1-R rather than AngII abolished the association of these two receptors. Ox-LDL-induced ERKs phosphorylation in LOX-1 and AT1-R-overexpression cells and the binding of both receptors were suppressed by the mutants of LOX-1 (Lys266Ala/Lys267Ala) or AT1-R (Glu257Ala), however, the AT1-R mutant lacking Gq protein-coupling ability only abolished the ERKs phosphorylation. The phosphorylation of ERKs induced by Ox-LDL in LOX-1 and AT1-R-overexpression cells was abrogated by Gq protein inhibitor but not by Jak2, Rac1 and RhoA inhibitors. Therefore, the direct interaction between LOX-1 and AT1-R and the downstream Gq protein activation are important mechanisms for Ox-LDL- but not AngII-induced cardiomyocyte hypertrophy

scholarly journals Functional human IgA targets a conserved site on malaria sporozoites

2021 ◽  
Vol 13 (599) ◽  
pp. eabg2344
Author(s):  
Joshua Tan ◽  
Hyeseon Cho ◽  
Tossapol Pholcharee ◽  
Lais S. Pereira ◽  
Safiatou Doumbo ◽  
...  
Keyword(s):  
Critical Role ◽  
Parasite Burden ◽  
Circumsporozoite Protein ◽  
Amino Terminus ◽  
Endemic Region ◽  
Serum Iga ◽  
Iga Response ◽  
Functional Antibodies ◽  
Mucosal Pathogens

Immunoglobulin (Ig)A antibodies play a critical role in protection against mucosal pathogens. However, the role of serum IgA in immunity to nonmucosal pathogens, such as Plasmodium falciparum, is poorly characterized, despite being the second most abundant isotype in blood after IgG. Here, we investigated the circulating IgA response in humans to P. falciparum sporozoites that are injected into the skin by mosquitoes and migrate to the liver via the bloodstream to initiate malaria infection. We found that circulating IgA was induced in three independent sporozoite-exposed cohorts: individuals living in an endemic region in Mali, malaria-naïve individuals immunized intravenously with three large doses of irradiated sporozoites, and malaria-naïve individuals exposed to a single controlled mosquito bite infection. Mechanistically, we found evidence in an animal model that IgA responses were induced by sporozoites at dermal inoculation sites. From malaria-resistant individuals, we isolated several IgA monoclonal antibodies that reduced liver parasite burden in mice. One antibody, MAD2-6, bound to a conserved epitope in the amino terminus of the P. falciparum circumsporozoite protein, the dominant protein on the sporozoite surface. Crystal structures of this antibody revealed a unique mode of binding whereby two Fabs simultaneously bound either side of the target peptide. This study reveals a role for circulating IgA in malaria and identifies the amino terminus of the circumsporozoite protein as a target of functional antibodies.

scholarly journals Kinetic Analysis of Binding Interaction between the Subgroup A Rous Sarcoma Virus Glycoprotein SU and Its Cognate Receptor Tva: Calcium Is Not Required for Ligand Binding

2003 ◽  
Vol 77 (13) ◽  
pp. 7517-7526 ◽  
Author(s):  
Xuemei Yu ◽  
Qing-Yin Wang ◽  
Ying Guo ◽  
Klavs Dolmer ◽  
John A. T. Young ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Rous Sarcoma Virus ◽  
Ldl Receptor ◽  
Viral Glycoprotein ◽  
Binding Interaction ◽  
Interaction Domain ◽  
High Association ◽  
Rous Sarcoma ◽  
Extracellular Region ◽  
Sarcoma Virus

ABSTRACT Tva is the receptor for subgroup A Rous sarcoma virus, and it contains a single LDL-A module which is the site of virus interaction. In this study, we expressed the entire extracellular region of Tva (referred to as Ecto-Tva) as a GST fusion protein and characterized its refolding properties. We demonstrated that the correct folding of the Ecto-Tva protein, like that of the Tva LDL-A module, is calcium dependent. We used the IAsys system to measure the kinetics of binding between the surface (SU) subunit of the viral glycoprotein and Tva in real time. We found that the Ecto-Tva protein and the Tva LDL-A module displayed similar affinities for SU, providing direct evidence that the LDL-A module of Tva is the only viral interaction domain of the receptor. Furthermore, misfolded Tva proteins displayed lower binding affinities to SU, largely due to a decrease in their association rates, suggesting that a high association rate between SU and Tva is crucial for efficient virus-host interaction. Furthermore, we found that calcium did not influence the overall binding affinity between Tva and SU. These results indicate that, although calcium is important in facilitating correct folding of the LDL-A module of Tva, it is not essential for ligand binding. Thus, these results may have broad implications for the mechanism of protein folding and ligand recognition of the LDL receptor and other members of the LDL receptor superfamily.

scholarly journals Role of Lectin-Like Oxidized Low Density Lipoprotein-1 in Fetoplacental Vascular Dysfunction in Preeclampsia

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Felipe A. Zuniga ◽  
Valeska Ormazabal ◽  
Nicolas Gutierrez ◽  
Valeria Aguilera ◽  
Claudia Radojkovic ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Dysfunction ◽  
Pathological Condition ◽  
Oxidized Ldl ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Fetal Loss ◽  
Density Lipoprotein ◽  
Placental Tissue

The bioavailability of nitric oxide (NO) represents a key marker in vascular health. A decrease in NO induces a pathological condition denominated endothelial dysfunction, syndrome observed in different pathologies, such as obesity, diabetes, kidney disease, cardiovascular disease, and preeclampsia (PE). PE is one of the major risks for maternal death and fetal loss. Recent studies suggest that the placenta of pregnant women with PE express high levels of lectin-like oxidized LDL receptor-1 (LOX-1), which induces endothelial dysfunction by increasing reactive oxygen species (ROS) and decreasing intracellular NO. Besides LOX-1 activation induces changes in migration and apoptosis of syncytiotrophoblast cells. However, the role of this receptor in placental tissue is still unknown. In this review we will describes the physiological roles of LOX-1 in normal placenta development and the potential involvement of this receptor in the pathophysiology of PE.

scholarly journals Three types of low density lipoprotein receptor-deficient mutant have pleiotropic defects in the synthesis of N-linked, O-linked, and lipid-linked carbohydrate chains.

1986 ◽  
Vol 102 (5) ◽  
pp. 1576-1585 ◽  
Author(s):  
D M Kingsley ◽  
K F Kozarsky ◽  
M Segal ◽  
M Krieger
Keyword(s):  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Genetic Defects ◽  
Low Density ◽  
Viral Glycoprotein ◽  
Essentially Normal ◽  
Density Lipoprotein Receptor ◽  
Glycolipid Synthesis ◽  
Carbohydrate Chains

Biochemical, immunological, and genetic techniques were used to investigate the genetic defects in three types of low density lipoprotein (LDL) receptor-deficient hamster cells. The previously isolated ldlB, ldlC, and ldlD mutants all synthesized essentially normal amounts of a 125,000-D precursor form of the LDL receptor, but were unable to process this receptor to the mature form of 155,000 D. Instead, these mutants produced abnormally small, heterogeneous receptors that reached the cell surface but were rapidly degraded thereafter. The abnormal sizes of the LDL receptors in these cells were due to defective processing of the LDL receptor's N- and O-linked carbohydrate chains. Processing defects in these cells appeared to be general since the ldlB, ldlC, and ldlD mutants also showed defective glycosylation of a viral glycoprotein, alterations in glycolipid synthesis, and changes in resistance to several toxic lectins. Preliminary structural studies suggested that these cells had defects in multiple stages of the Golgi-associated processing reactions responsible for synthesis of glycolipids and in the N-linked and O-linked carbohydrate chains of glycoproteins. Comparisons between the ldl mutants and a large number of previously isolated CHO glycosylation defective mutants showed that the genetic defects in ldlB, ldlC, and ldlD cells were unique and that only very specific types of carbohydrate alteration could dramatically affect LDL receptor function.

scholarly journals Critical role of oxidized LDL receptor-1 in intravascular thrombosis in a severe influenza mouse model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Marumi Ohno ◽  
Akemi Kakino ◽  
Toshiki Sekiya ◽  
Naoki Nomura ◽  
Masashi Shingai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tissue Injury ◽  
Oxidized Ldl ◽  
Critical Role ◽  
Elevated Serum ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Prothrombin Fragment ◽  
Intravascular Thrombosis ◽  
Severe Influenza

AbstractAlthough coagulation abnormalities, including microvascular thrombosis, are thought to contribute to tissue injury and single- or multiple-organ dysfunction in severe influenza, the detailed mechanisms have yet been clarified. This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model. After infecting C57BL/6 male mice with intranasal applications of 500 plaque-forming units of influenza virus A/Puerto Rico/8/34 (H1N1; PR8), an elevated serum level of prothrombin fragment 1 + 2, an indicator for activated thrombin generation, was observed. Also, an increased gene expression of oxidized low-density lipoprotein (LDL) receptor-1 (Olr1), a key molecule in endothelial dysfunction in the progression of atherosclerosis, was detected in the aorta of infected mice. Body weight decrease, serum levels of cytokines and chemokines, viral load, and inflammation in the lungs of infected animals were similar between wild-type and Olr1 knockout (KO) mice. In contrast, the elevation of prothrombin fragment 1 + 2 levels in the sera and intravascular thrombosis in the lungs by PR8 virus infection were not induced in KO mice. Collectively, the results indicated that OLR1 is a critical host factor in intravascular thrombosis as a pathogeny of severe influenza. Thus, OLR1 is a promising novel therapeutic target for thrombosis during severe influenza.

scholarly journals Extracellular HSP90α-LRP1 Signaling Promote Pancreatic Cancer Metastasis and Chemoresistance Via Regulating Epithelial-To-Mesenchymal Transition

2021 ◽  
Author(s):  
Nina Xue ◽  
Tingting Du ◽  
Fangfang Lai ◽  
Jing Jin ◽  
Ming Ji ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Underlying Mechanism ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Abstract Extracellular heat shock protein 90α (HSP90α) has been reported to promote cancer cell invasion and migration. However, whether pancreatic cancer (PC) cells expressed membrane-bound or secreted HSP90α and its underlying mechanism for PC progression were still unclear. Our study pointed out that highly invasive Capan2 cells has a higher level of secreted HSP90α, rather than membrane HSP90α, compared with those of less invasive PL45 cells. The conditioned medium of Capan2 cells or recombinant HSP90α protein was able to stimulate the migration and invasion of PL45 or capan2 cells, which could be prevented by a neutralizing anti-HSP90α antibody. Furthermore, secreted HSP90α promoted elements of epithelial-mesenchymal transition (EMT) in PL45 cells, including increases in vimentin and snail expressions, decreases in E-cadherin expression and changes in cell shape towards a mesenchymal phenotype, but these phenomena were reversed by anti-HSP90α antibody in Capan2 cells. In addition, high levels of low-density lipoprotein receptor-related protein 1 (LRP1) mRNA were associated with worsened patient survival in pancreatic adenocarcinoma. LRP1 as a receptor of eHSP90α for its stimulatory role of PC cells EMT and metastasis by activating AKT signaling. Down-regulation of LRP1 could promote chemosensitivity to gemcitabine and doxorubicin, but not to topotecan and paclitaxel in Capan2 cells. Therefore, our study reveals a critical role of secreted HSP90α on EMT events and suggests blocking secreted HSP90α underlies an aspect of metastasis and chemoresistance.

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