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Dusan Turk - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of the Soluble Form of equinatoxin ii a pore Forming toxin from the sea anemone actinia equina
Structure, 2001Co-Authors: Alekos Athanasiadis, Peter Macek, Gregor Anderluh, Dusan TurkAbstract:BACKGROUND: Membrane pore-Forming toxins have a remarkable property: they adopt a stable Soluble Form structure, which, when in contact with a membrane, undergoes a series of transFormations, leading to an active, membrane-bound Form. In contrast to bacterial toxins, no structure of a pore-Forming toxin from an eukaryotic organism has been determined so far, an indication that structural studies of equinatoxin II (EqtII) may unravel a novel mechanism. RESULTS: The crystal structure of the Soluble Form of EqtII from the sea anemone Actinia equina has been determined at 1.9 A resolution. EqtII is shown to be a single-domain protein based on a 12 strand beta sandwich fold with a hydrophobic core and a pair of alpha helices, each of which is associated with the face of a beta sheet. CONCLUSIONS: The structure of the 30 N-terminal residues is the largest segment that can adopt a different structure without disrupting the fold of the beta sandwich core. This segment includes a three-turn alpha helix that lies on the surface of a beta sheet and ends in a stretch of three positively charged residues, Lys-30, Arg-31, and Lys-32. On the basis of gathered data, it is suggested that this segment Forms the membrane pore, whereas the beta sandwich structure remains unaltered and attaches to a membrane as do other structurally related extrinsic membrane proteins or their domains. The use of a structural data site-directed mutagenesis study should reveal the residues involved in membrane pore Formation.
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crystal structure of the Soluble Form of equinatoxin ii a pore Forming toxin from the sea anemone actinia equina
Structure, 2001Co-Authors: Alekos Athanasiadis, Peter Macek, Gregor Anderluh, Dusan TurkAbstract:Abstract Background: Membrane pore–Forming toxins have a remarkable property: they adopt a stable Soluble Form structure, which, when in contact with a membrane, undergoes a series of transFormations, leading to an active, membrane-bound Form. In contrast to bacterial toxins, no structure of a pore-Forming toxin from an eukaryotic organism has been determined so far, an indication that structural studies of equinatoxin II (EqtII) may unravel a novel mechanism. Results: The crystal structure of the Soluble Form of EqtII from the sea anemone Actinia equina has been determined at 1.9 A resolution. EqtII is shown to be a single-domain protein based on a 12 strand β sandwich fold with a hydrophobic core and a pair of α helices, each of which is associated with the face of a β sheet. Conclusions: The structure of the 30 N-terminal residues is the largest segment that can adopt a different structure without disrupting the fold of the β sandwich core. This segment includes a three-turn α helix that lies on the surface of a β sheet and ends in a stretch of three positively charged residues, Lys-30, Arg-31, and Lys-32. On the basis of gathered data, it is suggested that this segment Forms the membrane pore, whereas the β sandwich structure remains unaltered and attaches to a membrane as do other structurally related extrinsic membrane proteins or their domains. The use of a structural data site-directed mutagenesis study should reveal the residues involved in membrane pore Formation.
Jorg C Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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decreased levels of a Soluble Form of the human adhesion receptor cd58 lfa 3 in sera and synovial fluids of patients with rheumatoid arthritis
Clinical and Experimental Rheumatology, 1996Co-Authors: Jorg C Hoffmann, H J Rauker, H Kruger, B Bayer, Henning ZeidlerAbstract:Objective. Soluble Forms of adhesion molecules (sAM) can block cellular interactions and potentially prevent the adhesion of mononuclear cells to inflammatory tissue. We therefore wondered whether levels of a Soluble Form of the CD2-ligand CD58 (sCD58) are decreased in patients with different types of joint disease. Methods. SCD58 concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) of sera from 60 patients with rheumatoid arthritis (RA), 13 patients with osteoarthritis (OA), 16 patients with psoriatic arthropathy (PsA), 15 patients with spondylarthropathy (SpA), and 61 age-matched normal controls (NC). SCD58 was also determined in synovial fluid samples (SF) from 42 patients with RA, 12 with PsA, and 12 with SpA. Concentrations of sCD58 were correlated with clinical and laboratory measures of disease activity. Binding of biotinylated human albumin to recombinant CD58 or casein was assessed by a modified ELISA. Results. SCD58 levels were significantly reduced in sera from RA patients compared to NC (p < 0.0001), OA (p = 0.019), and SpA (p < 0.0001). Normal concentrations were found in sera from patients with OA, PsA, or SpA. SF sCD58 concentrations were generally lower than serum concentrations (between 18 and 28%). RA SF had significantly lower sCD58 levels than SpA SF (p = 0.01). Reduction of serum sCD58 levels correlated significantly with the ESR (r = 0.56 ; p <0.0001), CRP (r = 0.4 ; p = 0.003), and TJS (r = 0.47 ; p = 0.0001). In addition, sCD58 serum levels correlated significantly with the reticulocyte count (r = 0.47 ; p = 0.02 and serum albumin (r = 0.42 ; p = 0.002). Accordingly, biotinylated human albumin bound to recombinant CD58 in a dose dependent fashion, but not to casein. Conclusion. This study indicates that serum and SF sCD58 levels in patients with RA are reduced compared to the levels in normal controls and patients with OA or SpA. Decreased albumin concentrations due to systemic inflammation may lead to reduced sCD58 levels. Since sCD58 may normally mediate de-adhesion, such a reduction could result in increased T cell adhesiveness.
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a Soluble Form of the adhesion receptor cd58 lfa 3 is present in human body fluids
European Journal of Immunology, 1993Co-Authors: Jorg C Hoffmann, Thomas J Dengler, Percy A Knolle, Marion Albertwolf, Matthias Roux, Reinhard Wallich, Stefan MeuerAbstract:The human adhesion receptor CD58 (LFA-3) is expressed on most human cell types. Here we report on a Soluble Form of CD58 (sCD58) in human serum, human urine, and culture supernatants of several cell lines. sCD58 partially purified from human serum, from supernatant of the Hodgkin cell line L428, and purified sCD58 from human urine were found to have a molecular mass of 40-70 kDa under denaturating conditions (sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting). However, gel filtration of sCD58 purified from human urine gave a molecular mass of 118-166 kDa, suggesting a noncovalent homotrimer conFormation or its association with other molecules. Using an enzyme-linked immunosorbent assay specific for CD58 we found that sera from patients suffering from different Forms of hepatitis contained elevated sCD58 levels (n = 108). Accordingly, there was a fivefold increase of supernatant sCD58 when the hepatocellular carcinoma cell line Hep G2 was incubated with 25 ng/ml recombinant tumor necrosis factor-alpha in vitro. In contrast, sCD58 serum levels of 337 additional patients suffering from various other immunological disorders were not found to be raised. At high concentrations sCD58 binds to CD2-positive cells and inhibits rosette Formation of human T cells to human erythrocytes. Thus, local release of large quantities of naturally occurring sCD58 may interfere with intercellular adhesion in vivo.
D I Stuart - One of the best experts on this subject based on the ideXlab platform.
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structure and dimerization of a Soluble Form of b7 1
Immunity, 2000Co-Authors: Shinji Ikemizu, E Y Jones, Karl Harlos, Robert J C Gilbert, J A Fennelly, A V Collins, D I StuartAbstract:B7-1 (CD80) and B7-2 (CD86) are glycoproteins expressed on antigen-presenting cells. The binding of these molecules to the T cell homodimers CD28 and CTLA-4 (CD152) generates costimulatory and inhibitory signals in T cells, respectively. The crystal structure of the extracellular region of B7-1 (sB7-1), solved to 3 A resolution, consists of a novel combination of two Ig-like domains, one characteristic of adhesion molecules and the other previously seen only in antigen receptors. In the crystal lattice, sB7-1 unexpectedly Forms parallel, 2-fold rotationally symmetric homodimers. Analytical ultracentrifugation reveals that sB7-1 also dimerizes in solution. The structural data suggest a mechanism whereby the avidity-enhanced binding of B7-1 and CTLA-4 homodimers, along with the relatively high affinity of these interactions, favors the Formation of very stable inhibitory signaling complexes.
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crystal structure at 2 8 a resolution of a Soluble Form of the cell adhesion molecule cd2
Nature, 1992Co-Authors: E Y Jones, Simon J Davis, Alan F Williams, Karl Harlos, D I StuartAbstract:The crystal structure of a Soluble Form of the T lymphocyte antigen CD2 provides the first complete view of the extracellular region of a cell adhesion molecule. The topology of the molecule, which comprises two immunoglobulin-like domains, is the same as that of the first two domains of CD4 but the relative domain orientation is altered by a fairly flexible linker region. The putative ligand-binding β-sheet Forms a flat surface towards the top of the molecule. Crystal contacts between these surfaces suggest a plausible model for the adhesive interaction.
Tsutomu Imaizumi - One of the best experts on this subject based on the ideXlab platform.
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circulating advanced glycation end products ages and Soluble Form of receptor for ages srage are independent determinants of serum monocyte chemoattractant protein 1 mcp 1 levels in patients with type 2 diabetes
Diabetes-metabolism Research and Reviews, 2008Co-Authors: Kazuo Nakamura, Shoichi Yamagishi, Hisashi Adachi, Yayoi Kuritanakamura, Takanori Matsui, Masayoshi Takeuchi, Hiroyoshi Inoue, Tsutomu ImaizumiAbstract:Background Atherosclerosis is an inflammatory disease. Monocyte chemoattractant protein-1 (MCP-1) is an essential chemokine responsible for the recruitment of monocytes to inflammatory lesions in the vasculature, an initial step of atherosclerosis. Since serum levels of MCP-1 are higher in patients with type 2 diabetes, inhibition of MCP-1 may be a novel therapeutic target for prevention of accelerated atherosclerosis in diabetes. However, little is known about the regulation and determinants of serum MCP-1 levels in patients with diabetes. In this study, we examined the determinants of serum MCP-1 levels in type 2 diabetic patients. Methods Eighty-six consecutive outpatients with type 2 diabetes (36 male and 50 female; mean age 68.4 ± 9.6) underwent a complete history and physical examination, determination of blood chemistries, MCP-1, tumour necrosis factor-α, adiponectin, advanced glycation end products (AGEs), and Soluble Form of receptor for AGEs (sRAGE). We examined the association between MCP-1 levels and those in anthropometric, metabolic and inflammatory variables in these subjects. Results Univariate regression analysis showed that serum levels of MCP-1 were positively associated with AGEs (r = 0.386, p < 0.001) and sRAGE (r = 0.315, p < 0.001). After adjusting for age and sex, AGEs (p < 0.001) and sRAGE (p < 0.05) still remained significant. Conclusion The results demonstrate for the first time that circulating levels of AGEs and sRAGE are independent determinants of serum MCP-1 levels in patients with type 2 diabetes. Our present observations suggest the AGEs-RAGE system may be mainly involved in the elevation of MCP-1 in type 2 diabetic patients. Copyright © 2007 John Wiley & Sons, Ltd.
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elevation of Soluble Form of receptor for advanced glycation end products srage in diabetic subjects with coronary artery disease
Diabetes-metabolism Research and Reviews, 2007Co-Authors: Kazuo Nakamura, Shoichi Yamagishi, Hisashi Adachi, Yayoi Kuritanakamura, Takanori Matsui, Takafumi Yoshida, Akira Sato, Tsutomu ImaizumiAbstract:Background Advanced glycation end products (AGEs)-receptor (RAGE) axis is implicated in diabetic vascular complication. Since a Soluble Form of RAGE (sRAGE) could be generated from the cleavage of cell surface RAGE in endothelial cells (ECs), serum sRAGE levels may be elevated in diabetes consequent to EC damage. In this study, we examined whether sRAGE levels were elevated in type 2 diabetic patients compared with non-diabetic healthy subjects. Methods Serum sRAGE levels were examined in 75 Japanese type 2 diabetic patients (29 men and 46 women; mean age 66 ± 11 years) and 75 age- and sex-matched non-diabetic healthy control subjects. We explored the association between sRAGE levels and coronary artery disease (CAD) in diabetic patients. Results Serum sRAGE levels were significantly higher in diabetic patients than in non-diabetic subjects (965.3 ± 544.2 vs 415 ± 150.4 pg/mL, p < 0.001). In the univariate analysis, diastolic blood pressure (inversely), LDL cholesterol, triglycerides, HDL cholesterol, hemoglobin A1c, and creatinine were significantly associated with sRAGE. After perForming multivariate analyses, the presence of diabetes (p < 0.0001) was a sole independent determinant of sRAGE. Furthermore, there was a significant difference in sRAGE levels between diabetic patients with CAD and those without CAD (1680.6 ± 891.1 vs 855.2 ± 372.1 pg/mL, p < 0.001). Multiple stepwise regression analysis revealed that sRAGE and creatinine levels were independent determinants of CAD. Conclusions The present study demonstrated that serum sRAGE levels were significantly higher in type 2 diabetic patients than in non-diabetic subjects and positively associated with the presence of CAD. Copyright © 2006 John Wiley & Sons, Ltd.
Marco Bianchi - One of the best experts on this subject based on the ideXlab platform.
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a Soluble Form of the receptor for advanced glycation endproducts rage is produced by proteolytic cleavage of the membrane bound Form by the sheddase a disintegrin and metalloprotease 10 adam10
The FASEB Journal, 2008Co-Authors: Angela Raucci, Simona Cugusi, Antonella Antonelli, Silvia M L Barabino, Lucilla Monti, Angelika Bierhaus, Karina Reiss, Paul Saftig, Marco BianchiAbstract:The receptor for advanced glycation endproducts (RAGE) mediates responses to cell danger and stress. When bound by its many ligands (which include advanced glycation endproducts, certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid β-peptide and fibrils), RAGE activates programs responsible for acute and chronic inflammation. RAGE is therefore also involved in cancer progression, diabetes, atherosclerosis, and Alzheimer’s disease. RAGE has several isoForms deriving from alternative splicing, including a Soluble Form called endogenous secretory RAGE (esRAGE). We show here that most Soluble RAGE, either produced by cell lines or present in human blood, is not recognized by an anti-esRAGE antibody. Cells transfected with the cDNA for full-length RAGE, and thus not expressing esRAGE, produce a Form of Soluble RAGE, cleaved RAGE (cRAGE) that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. By screenin...
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A Soluble Form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound Form by the sheddase a disintegrin and metalloprotease 10 (ADAM10)
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2008Co-Authors: Angela Raucci, Simona Cugusi, Antonella Antonelli, Silvia M L Barabino, Lucilla Monti, Angelika Bierhaus, Karina Reiss, Paul Saftig, Marco BianchiAbstract:The receptor for advanced glycation endproducts (RAGE) mediates responses to cell danger and stress. When bound by its many ligands (which include advanced glycation endproducts, certain members of the S100/calgranulin family, extracellular high-mobility group box 1, the integrin Mac-1, amyloid beta-peptide and fibrils), RAGE activates programs responsible for acute and chronic inflammation. RAGE is therefore also involved in cancer progression, diabetes, atherosclerosis, and Alzheimer's disease. RAGE has several isoForms deriving from alternative splicing, including a Soluble Form called endogenous secretory RAGE (esRAGE). We show here that most Soluble RAGE, either produced by cell lines or present in human blood, is not recognized by an anti-esRAGE antibody. Cells transfected with the cDNA for full-length RAGE, and thus not expressing esRAGE, produce a Form of Soluble RAGE, cleaved RAGE (cRAGE) that derives from proteolytic cleavage of the membrane-bound molecules and acts as a decoy receptor. By screening chemical inhibitors and genetically modified mouse embryonic fibroblasts (MEFs), we identify the sheddase ADAM10 as a membrane protease responsible for RAGE cleavage. Binding of its ligand HMGB1 promotes RAGE shedding. Our data do not disprove the interpretation that high levels of Soluble Forms of RAGE protect against chronic inflammation, but rather suggest that they correlate with high levels of ongoing inflammation.
