The type I and type II bovine scavenger receptors expressed in Chinese hamster ovary cells are trimeric proteins with collagenous triple helical domains comprising noncovalently associated monomers and Cys83-disulfide-linked dimers (original) (raw)
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Proceedings of the National Academy of Sciences, 1991
Type I and type II scavenger receptors, which have been implicated in the development of atherosclerosis and other macrophage-associated functions, differ only by the presence in the type I receptor of an extracellular cysteine-rich C-terminal domain. Stable Chinese hamster ovary (CHO) cell transfectants expressing high levels of either the type I or type II bovine scavenger receptors have been generated. Type I and type II receptors in these cells mediated high-affinity saturable endocytosis of both 125I-labeled acetylated low density lipoprotein (LDL) and 125I-labeled oxidized LDL with the distinctive broad ligand specificity characteristic of scavenger receptors. After incubation for 2 days with acetylated LDL, the transfected cells accumulated oil red O-staining lipid droplets reminiscent of those in macrophage foam cells, whereas untransfected CHO cells did not. Thus, macrophage-specific gene products other than the scavenger receptor are not required for modified-LDL-induced i...
Journal of Biological Chemistry, 2004
The class A scavenger receptor (SR-A) is a multifunctional trimeric membrane glycoprotein involved in atherogenesis. The mature receptor can mediate the binding and internalization of a number of specific ligands, including modified low-density lipoprotein. We have investigated the effects of inhibiting N-glycan processing on SR-A expression, distribution, and activity in the murine macrophage cell line RAW264.7. We have found that SR-A normally interacts with calnexin in the endoplasmic reticulum and in its mature form carries complex N-glycans. The imino sugar, N-butyldeoxynojirimycin (NB-DNJ) is an inhibitor of the N-glycan processing enzymes ␣-glucosidases I and II. Following NB-DNJ treatment SR-A became Endo H-sensitive, consistent with inhibition of N-glycan processing. A dose-dependent increase in cell surface expression of SR-A was observed in response to NB-DNJ treatment. The receptor on inhibitor-treated cells was still functional because the increased surface expression resulted in a proportional enhancement in the endocytosis of the ligand, acetylated low-density lipoprotein. The expression of SR-A on NB-DNJ cultured cells was further enhanced by co-treatment with interferon-␥. Quantitative reverse transcriptase-PCR analysis did not show a significant difference in the amount of SR-A mRNA in NB-DNJ-treated RAW264.7 cells. However, the half-life of SR-A protein was significantly increased. These data indicate the retention of glucosylated N-glycans does not result in gross misfolding and degradation of this receptor or prevent its transport to the cell surface. SR-A interacts with calnexin and when the association is prevented changes in the recycling kinetics and rate of turnover of the receptor result, leading to enhanced cell surface expression.
Scavenger Receptors and Modified Lipoproteins: Fatal Attractions?
IUBMB Life (International Union of Biochemistry and Molecular Biology: Life), 2000
Lipoproteins modi ed by oxidation, glycation, alkylation, and nitration are generated by oxidative stress during in ammation, diabetes, and inadequate supply of dietary antioxidants. A family of genes, the scavenger receptors, recognizes and internalizes modi ed lipoproteins, making them susceptible to degradation.
Oxidative stress impairs endocytosis of the scavenger receptor class A
Biochemical and Biophysical Research Communications, 2003
We report the characterization of a cell system employing Chinese hamster ovary (CHO) cells and CHO cells transfected with the scavenger receptor class A (CHO-SRA) using extracellularly produced reactive oxygen species (ROS) in order to study the endocytic function of the scavenger receptor. The oxidative environment was produced using tert-butyl hydroperoxide (TBH) and characterized by flow cytometry and cell viability. Once an adequate oxidative environment was established, binding and internalization studies of radiolabeled acetylated LDL particles ( 125 I-labeled Ac-LDL) with CHO-SRA cells were carried out. RT-PCR analysis using total RNAs from CHO-SRA cells revealed that oxidative stress does not alter the expression of the scavenger receptor. However, internalization of 125 I-labeled Ac-LDL through this receptor carried out by these cells was completely abolished under extracellularly oxidative conditions. Together, these results support the idea that an oxidative stress produced extracellularly, inhibiting the endocytosis of the scavenger receptor, could help to understand and explain the mechanisms by which several physiologically important ligands are accumulated in the extracellular space with its consequent cell damage.
Molecular Pharmacology, 2005
Scavenger receptors on sinusoidal liver endothelial cells (SECs) eliminate potentially harmful modified proteins circulating through the liver. It was shown recently that aldehyde-modified proteins bind to scavenger receptors and are associated with the development/progression of alcoholic liver diseases. For these studies, rat livers were perfused in situ with 125 I-formaldehyde-bovine serum albumin (f-Alb) or 125 I-malondialdehydeacetaldehyde-bovine serum albumin (MAA-Alb) in the presence of known scavenger receptor ligands as inhibitors. Reverse transcription-polymerase chain reaction (RT-PCR) analysis and scavenger receptor Type A (SRA) knockout mice were used to assess the role of these receptors in mediating immune responses. The degradation of 125 If -Alb or 125 I-MAA-Alb in whole livers and isolated SECs can be inhibited by known scavenger receptor ligands, including f-Alb, maleylated bovine albumin, and fucoidan. 125 If -Alb could not be completely inhibited by MAA-Alb. In contrast, 125 I-MAA-Alb was only partially inhibited with advanced glycosylated endproduct albumin. RT-PCR data show the presence of a number of scavenger receptors on SECs that may be responsible for the binding of MAA-modified proteins. SRA seems to be one of these receptors involved in the effects mediated by MAA-modified proteins. In a study using SRA knockout mice, it was shown that a decreased antibody response to MAA-Alb resulted. By RT-PCR, CD36, LOX-1, and SR-AI are the scavenger receptors most likely involved in the degradation of MAA-Alb. Scavenger receptors were first described in macrophage as alternative receptors for the low-density lipoprotein receptor that is responsible for the uptake of excessive cholesterol, leading to the formation of foam cells (Terpstra et al., 2000). Since this original description, a broad array of ligands for several classes of scavenger receptors have been described previously (Terpstra et al., 2000). In general, organic acid anhydrides, peroxides, and aldehydes (Brown et al., 1980) result in the modification of positively charged lysine resi
Biochemical Journal, 1988
Membranes from rat liver were analysed under reducing conditions. The components of the soluble membranes responsible for the binding of acetylated low density lipoprotein (acetyl-LDL) and maleylated bovine serum albumin (Mal-BSA) were chromatographed on a polyethyleneimine-cellulose column and subsequently separated by gel electrophoresis. For both ligands a major binding protein (Mr = 35,000) was revealed by ligand blotting. A minor protein (Mr greater than 67,000) exhibited little binding. The Scatchard plot of the 131I-Mal-BSA binding data of the 35 kDa protein was linear, with a Kd of 17.3 nM. High concentrations of acetyl-LDL competed for half of the 131I-Mal-BSA binding. Excessive Mal-BSA competed for all the visible acetyl-LDL binding. The findings indicate the existence, in the reduced hepatic membrane, of a 35 kDa protein that has two binding sites for 131I-Mal-BSA and one binding site for acetyl-LDL.
Scavenger receptors: a key player in cardiovascular diseases
BioMolecular Concepts, 2012
The scavenger receptor (SR) super family consists of integral membrane glycoproteins that are involved in recognition of polyanionic structures of either endogenous (e.g., oxidized low-density lipoprotein) or exogenous (e.g., bacterial lipopolysaccharides) origin. SRs are structurally diverse and can be classified into seven different classes (A–G) based on the multidomain structure of the individual members. SRs are present on various types of tissues, such as vascular, adipose, and steroidogenic tissues. In addition to modified lipoprotein uptake, these proteins are also known to regulate apoptotic cell clearance, initiate signal transduction, and serve as pattern recognition receptors for pathogens. Different SRs are involved in many physiological and pathological processes; more importantly, the function of SRs is highly implicated in the initiation and progression of atherosclerotic plaque. Targeting the SR gene products that mediate the response to and uptake of modified lipid...
Macrophages adhere to glucose-modified basement membrane collagen IV via their scavenger receptors
Journal of Biological Chemistry, 1994
Scavenger receptors have been reported to mediate macrophage adhesion to serum-coated plastic surfaces. W e report here that scavenger receptors promote the divalent cation independent adhesion of human monocytes and macrophages to surfaces coated with non-enzymatically glycated collagen IV but not to surfaces coated with native collagen IV. Ligands for scavenger receptor types I and II blocked adhesion of monocytes and macrophages to non-enzymatically glycated collagen IV but had no effect on adhesion of these cells to albumin-coated surfaces. US37 human promonocyte-like cells transfected with cDNA encoding bovine scavenger receptor I or I1 adhered to surfaces coated with glycated-collagen IV but not to surfaces coated with native collagen IV. A synthetic peptide homologous to the domain of bovine scavenger receptor that binds modified low density lipoproteins (residues 327-343) inhibited the adhesion of U937 cells transfected with cDNA encoding bovine scavenger receptor 11 to glycated collagen IV, whereas a control peptide from the a helical domain of scavenger receptor I1 (residues 121-137) had no effect on adhesion of these cells. Macrophages plated on surfaces coated with glycated collagen IV were unable to endocytose acetylated low density lipoproteins from the medium, suggesting that their scavenger receptors were occupied in binding these cells to the substrate. These findings suggest new roles for scavenger receptors in the accelerated development of vascular lesions observed in diabetics. ~ ~~ Mononuclear phagocytes express scavenger receptors (SRs)' that promote endocytosis and degradation of modified low density lipoproteins (1). Two types of SRs have been identified and cloned (2, 3). Both types are homotrimeric membrane glyco
Annals of the New York Academy of Sciences, 2006
Scavenger-receptor class A has been held responsible for the clearance of modified LDL from the blood circulation. However, in mice deficient in scavenger-receptor class A, the decay in vivo of acetylated LDL (t ½ < 2 min), as well as tissue distribution and liver uptake (at 5 min 77.4 ë6 4.6% of the injected dose) are not significantly different from control mice. The degradation capacity of acetylated LDL with liver endothelial cells, Kupffer cells, and peritoneal macrophages from knock-out mice was 58%, 63%, and 17% of the control, respectively, indicating that scavenger-receptor class A is relatively more important for the degradation of acetylated LDL and foam cell formation in peritoneal macrophages as compared to the liver cell types. This might explain the 60% reduction in atherosclerotic lesion area in scavenger-receptor-deficient apoE knock-out mice as compared to control apoE knock-out mice. Scavenger-receptor BI can facilitate selective uptake of cholesterol esters from HDL. A high cholesterol diet for two weeks induced an 80% downregulation of scavenger-receptor BI in the liver parenchymal cells while expression in liver macrophages is increased fourfold. The in vivo kinetics for the selective uptake of (oxidized) cholesterol esters from HDL correlate with the changes in scavenger-receptor BI expression. It is suggested that scavenger-receptor BI is subject to different regulatory mechanisms in parenchymal liver cells and macrophages related to a difference in function in these cell types.