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PubMedDate not supplied

Architecture of native human alpha 2-macroglobulin studied by cryoelectron microscopy and three-dimensional reconstruction.

The architecture of the native human alpha 2-macroglobulin was studied by cryoelectron microscopy and image processing techniques. The lip, padlock, doughnut, and four-petaled flower views of this homotetrameric proteinase inhibitor were observed in the frozen-hydrated specimen, and a new view, termed eye view, was also characterized. The present three-dimensional reconstruction demonstrates that all these electron microscope views derive from a single three-dimensional structure. The molecule is composed of two horizontal bodies and of two oblique arches, which border a large central cavity. The polymorphism and the flexibility of the native alpha 2-macroglobulin are discussed.

Freezing↗
PubMed1994

Serum alpha 1-antitrypsin and alpha 2-macroglobulin in Alzheimer's and Binswanger's disease.

The deposition of beta A4-amyloid in senile plaques and small cerebral vessels is one of the pathological hallmarks of Alzheimer's disease. Recent data suggest that protease inhibitors such as alpha 2-macroglobulin may be involved in the process of forming beta A4 amyloid deposits. Compared to 34 persons without neurological diseases, the serum content of alpha 1-antitrypsin was increased in 16 patients with Alzheimer's disease and 15 with Binswanger's disease. In the latter alpha 2-macroglobulin was also elevated in serum. Our results show no evidence of a blood-borne origin of the protein or peptid deposited in the walls of small vessels in Alzheimer's or Binswanger's disease. Nevertheless, the elevated proteinase inhibitor concentrations may play a role in the pathogenesis of these diseases.

Aged↗
PubMed1983

Alpha 1-antitrypsin, alpha 2-macroglobulin and complement C4 in human benign prostatic hyperplasia.

The concentrations of the globulins alpha 1-antitrypsin, alpha 2-macroglobulin and complement C4 have been determined in tissue samples of benign prostatic hyperplasia, from patients with and without prior treatment before open surgery. Globulins have been determined by means of radial immunodiffusion. Results obtained show that alpha 1-antitrypsin is present in high concentrations in human prostate. Treatment with anti-androgens influences the alpha 2-macroglobulin concentration in the different prostatic lobes. Complement C4 concentration is not influenced by the treatment.

Androgen Antagonists↗
PubMed1985

Characterization of a half-molecular fragment obtained by reduction of human alpha 2-macroglobulin with dithiothreitol. A small-angle X-ray and neutron scattering investigation.

A half-molecular fragment of alpha 2-macroglobulin has been prepared by reducing and alkylating the inter-subunit disulfide bonds in the tetrameric alpha 2-macroglobulin molecule with 1 mM dithiothreitol (40 min) and 3 mM iodoacetamide (40 min). Further purification was made by gel chromatography and the homogeneous population of half-molecules has been characterized by the techniques of small-angle X-ray and neutron scattering. The radii of gyration found by the two methods are 57.0 and 58.0 A, respectively. The match point, obtained by neutron scattering from solutions with different H2O/D2O ratios, is at 43% D2O; the data are consistent with a particle having a higher scattering density at large distances from the particle centre. From the X-ray and neutron intensities scattered at zero angle, the specific volume was determined to be 0.73 cm3/g at +5 degrees C and the molecular weight to be 390,000; the latter value is associated with a relatively large error due to the uncertainty in the concentration determination. Shape analysis indicates that the best-fitting scattering-equivalent three-axial bodies are oblate shaped, with two of their axial dimensions about three to four times larger than the third one. From the volume of the best-fitting scattering-equivalent three-axial bodies, 0.72 X 10(6) A3, we obtain a water content equal to 0.38 g H2O/g protein (dry weight).

Dithiothreitol↗
PubMed1993

Abnormal glycosylation of alpha 2-macroglobulin, a non-acute-phase protein in patients with autoimmune diseases.

Previous studies from this and other laboratories have shown that abnormal glycosylation of several acute-phase proteins can be detected in various pathological conditions including autoimmune diseases. In the present study, we have investigated if abnormal glycosylation is limited to acute-phase proteins. We used the concanavalin A (Con A) blots in conjunction with the peptide mapping techniques to analyze serum samples and cerebrospinal fluids (CSF) obtained from patients with autoimmune diseases: systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed connective tissue disease (MCTD), scleroderma (SCL), Sjögren's syndrome (SS), and polymyositis (PM); diseases of probable autoimmune origin: hepatopathies (HP); diseases of suspected autoimmune origin: schizophrenia and Alzheimer's disease (AZ); and conditions not related to autoimmunity: pregnancy (PG) and elevation of the carcinoembryonic antigen (CEA), in comparison to normal donors (NHS). We have micropurified two human proteins; alpha 2-macroglobulin, a non-acute-phase protein and beta-chain of haptoglobin, a known acute-phase protein, from serum samples of individual patients with SLE, RA, MCTD, SCL and SS, and from PG and NHS for analysis. The identity of the purified proteins was confirmed by immunoblots using either monospecific polyclonal or monoclonal antibodies, and by direct N-terminal amino acid sequencing. Peptide maps for each of these proteins were generated using Staphylococcus aureus protease V8, a Glu-C endopeptidase. When the peptide fragments of alpha 2-macroglobulin were resolved by SDS-PAGE and visualized using silver staining, no differences were noted between patient samples and controls. However, when they were examined by lectin blots using Con A, the Con A-reactive fragments increased specifically and significantly in samples derived from patients of SLE, SCL, MCTD, and RA. Similarly when the peptide fragments of the beta-chain of haptoglobin were visualized by silver staining, no differences were noted; however, the Con A reactivity of specific fragments increased in SLE, RA, SCL, and SS patients. Analysis of these results indicated that there has been a selective increase in Con A-reactive fragments in both acute-phase and non-acute-phase proteins in autoimmune conditions. Thus, the study of changes in glycosylation patterns in selected serum proteins may be a valuable diagnostic approach to define the pathophysiology of inflammatory and autoimmune disorders.

Acute-Phase Proteins↗
PubMed1980

Inhibition of neutrophil-mediated cytotoxicity by alpha 2 macroglobulin.

Highly purified human alpha 2 macroglobulin (1.2--10 mg/ml) was shown to inhibit phytohemagglutinin-induced or antibody-induced lysis of chicken erythrocytes by polymorphonuclear neutrophils. Inhibition was not associated with impaired contact between effector and target cells but rather with the antiprotease activity of alpha 2 macroglobulin.

Animals↗
PubMed1987

Caeruloplasmin, prealbumin and alpha 2-macroglobulin as potential indices of disease activity in different arthritides.

Caeruloplasmin (Cp), prealbumin and alpha 2-macroglobulin (alpha 2-M) concentrations in serum were compared in rheumatoid arthritis (RA), osteoarthrosis, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, Behçet's syndrome, SLE and normal controls. Cp was significantly elevated (p less than 0.01) in all disease groups except for Reiter's syndrome and SLE. Prealbumin was only significantly depressed (p less than 0.01) in RA. The most notable elevation in alpha 2-macroglobulin occurred in Reiter's syndrome. However, these differences were generally still within the normal range, and hence these proteins are unlikely to offer alternative indices of disease activity suitable for monitoring the the progress of seronegative arthropathies.

Arthritis↗
PubMed1996

Plasminogen modulation of IL-1-stimulated degradation in bovine and human articular cartilage explants. The role of the endogenous inhibitors: PAI-1, alpha 2-antiplasmin, alpha 1-PI, alpha 2-macroglobulin and TIMP.

The studies described here examine the involvement of the fibrinolytic cascade and its endogenous inhibitors in the regulation of activity of matrix metalloproteinases and cartilage degradation related to non-inflammatory joint disease, like osteoarthritis. An interleukin-1-induced model of degradation using [35S]-labeled bovine and human articular cartilage explants was utilized. One goal of these studies was to compare the responses of bovine and human articular cartilage. Degradation was not inhibited by alpha 1-PI, PAI-1, alpha 2-macroglobulin, alpha 2-antiplasmin or TIMP-2, when IL-1 alone was added. Addition of human plasminogen to bovine explants, at concentrations found in human synovial fluid, increased degradation by three to four-fold. Under these conditions, the degradation was inhibited effectively by all of the endogenous inhibitors tested, indicating the presence of a cascade where activated chondrocytes are a source of u-PA. Plasminogen activated by u-PA gives plasmin, which is known to further activate pro-stromelysin. Stromelysin is essential for activation of collegenase. Not only TIMP, but also inhibitors at earlier steps of activation like PAI-1, alpha 2-antiplasmin, alpha 1-PI and alpha 2-macroglobulin inhibited degradation, and could provide cartilage protection in vivo. An experiment with human articular cartilage explants showed that very little or no degradation occurred when human articular cartilage explants were stimulated with interleukin-1 alone. Addition of human plasminogen (at physiologically relevant concentrations) resulted in significant degradation, which was inhibited in the same manner as in bovine explants, by inhibitors of the fibrinolytic cascade and TIMP. TIMP is much more efficient in human explants, indicating the limited participation of human plasmin in the degradation of human cartilage. Although speculative, it is possible that in vivo, cartilage degradation could be promoted not only by TIMP/MMP imbalance, but also accelerated by decreased levels of certain serpins in synovial fluid (e.g. PAIs, alpha 2-antiplasmin and alpha 1-PI).

Animals↗
PubMed1988

Localization of alpha 2-macroglobulin in human primary sarcomas and synthesis in established cell lines.

The presence of alpha 2-macroglobulin (alpha 2M) was detected with the avidin-biotin technique in more than 20-yr-old paraffin blocks from human sarcomas. alpha 2M was found mainly in the cytoplasm of the tumor cells, and almost all tumor cells were positive. This serum glycoprotein, which is a major plasma proteinase inhibitor with a wide specificity, was also shown to be synthesized and secreted by all three cell lines derived from primary sarcomas but was not detected in cultures of the autologous skin fibroblasts. For the detection of alpha 2M in situ and in vitro an antiserum to tumor-associated alpha 2-macroglobulin was used.

Cell Line↗
PubMed2003

Direct injection and expression in vivo of full-length cDNA of the cardiac isoform of alpha-2 macroglobulin induces cardiac hypertrophy in the rat heart.

Earlier studies from this laboratory have shown that the serum protein of molecular weight of 182 kDa, which plays an indispensable role in the development of cardiac hypertrophy, may be a cardiac isoform of alpha-2 macroglobulin belonging to macroglobulin family (36). Furthermore, reports on the stable expression in vivo of several reporter genes injected directly into the myocardium of rat and the approach of direct gene transfer into adult mammalian heart to characterize the activity of a cellular gene and to modulate overall cardiac function in vivo prompted us to evaluate the hypertrophy inducing potential of a full-length cDNA for the 182 kDa protein upon direct injection. The full-length cDNA of the cardiac isoform of alpha-2 M obtained from hypertrophied rat heart mRNA and cloned in an eukaryotic expression vector namely pcDNA 3.1(-) was injected directly into the rat heart; the protein whose expression was constitutively triggered by the cytomegaloviral promoter could be detected in the serum of the injected animals and it could exert its function of inducing the hypertrophy, by a highly plausible way, by which the cardiac specific 182 kDa protein may bind to many growth modulating factors in the serum, and then be targeted to cardiomyocytes by a receptor mediated mechanism (36). The development of cardiac hypertrophy was monitored by determining the heart weight-body weight ratio. This ratio along with Northern blot analysis of muscle specific marker genes such as beta-MHC, MLC-2 and ANF, and the induction of promoter activity of beta-MHC and c-fos genes monitored using chloramphenicol acetyl transferase as a reporter gene confirmed the induction of cardiac hypertrophy upon direct injection of the full-length cDNA of 182 kDa protein.

Amino Acid Sequence↗
PubMed1986

In vivo metabolism of inter-alpha-trypsin inhibitor and its proteinase complexes: evidence for proteinase transfer to alpha 2-macroglobulin and alpha 1-proteinase inhibitor.

Inter-alpha-trypsin inhibitor was purified by a modification of published procedures which involved fewer steps and resulted in higher yields. The preparation was used to study the clearance of the inhibitor and its complex with trypsin from the plasma of mice and to examine degradation of the inhibitor in vivo. Unlike other plasma proteinase inhibitor-proteinase complexes, inter-alpha-trypsin inhibitor reacted with trypsin did not clear faster than the unreacted inhibitor. Studies using 125I-trypsin provided evidence for the dissociation of complexes of proteinase and inter-alpha-trypsin inhibitor in vivo, followed by rapid removal of proteinase by other plasma proteinase inhibitors, particularly alpha 2-macroglobulin and alpha 1-proteinase inhibitor. Studies in vitro also demonstrated the transfer of trypsin from inter-alpha-trypsin inhibitor to alpha 2-macroglobulin and alpha 1-proteinase inhibitor but at a much slower rate. The clearance of unreacted 125I-inter-alpha-trypsin inhibitor was characterized by a half-life ranging from 30 min to more than 1 h. Murine and human inhibitors exhibited identical behavior. Multiphasic clearance of the inhibitor was not due to degradation, aggregation, or carbohydrate heterogeneity, as shown by competition studies with asialoorosomucoid and macroalbumin, but was probably a result of extravascular distribution or endothelial binding. 125I-inter-alpha-trypsin inhibitor cleared primarily in the liver. Analysis of liver and kidney tissue by gel filtration chromatography and sodium dodecyl sulfate gel electrophoresis showed internalization and limited degradation of 125I-inter-alpha-trypsin inhibitor in these tissues. No evidence for the production of smaller proteinase inhibitors from 125I-inter-alpha-trypsin inhibitor injected intravenously or intraperitoneally was detected, even in casein-induced peritoneal inflammation. No species of molecular weight similar to that of urinary proteinase inhibitors, 19,000-70,000, appeared in plasma, liver, kidney, or urine following injection of inter-alpha-trypsin inhibitor.

Alpha-Globulins↗
PubMed1995

Salivary levels of alpha 2-macroglobulin, alpha 1-antitrypsin, C-reactive protein, cathepsin G and elastase in humans with or without destructive periodontal disease.

Five host-response indicators were measured by enzyme-linked immunosorbent assays on unstimulated whole saliva samples from 45 adults (19 male, 26 female). The participants were distributed among four dentate groups representing oral health (I), gingivitis (II), moderate periodontitis (III), and severe periodontitis (IV), and one group of edentulous volunteers (V). Levels of the host-response indicators varied widely, from zero, primarily with groups I and V, to relatively high values with groups II, III and IV. The levels ranged as follows: alpha 2-macroglobulin, 0-4941 ng/ml; alpha 1-antitrypsin, 2-2271 ng/ml; C-reactive protein, 0-472 pg/ml; cathepsin G, 0-6035 ng/ml; elastase, 0-164 ng/ml (free), 0-732 ng/ml (bound to alpha 1-antitrypsin), and 0-318 ng/ml (bound to alpha 2-macroglobulin). Statistical evaluation by planned contrasts showed that levels of host-response indicators for group I were significantly lower (except for alpha 1-antitrypsin) than for groups II, III, and IV. A trend analysis of groups I-IV showed that mean scores (again, except for alpha 1-antitrypsin) increased significantly in a positive, monotonic manner. Group V showed significantly lower values for elastase than in the other groups. The findings demonstrate that these factors can be detected in whole saliva and suggest that, except for alpha 1-antitrypsin, their levels are directly related to an individual's periodontal status.

Adult↗
PubMed1983

Localization of the proteinase-induced thiol groups in alpha 2-macroglobulin.

Free thiol groups released on proteolytic attack of alpha 2-macroglobulin by trypsin or chymotrypsin bind covalently to thiopropyl-Sepharose, indicating that they are located at the surface of the complexes. These cysteine sulfhydryl groups appear to be in contact with the alpha 2M-bound proteases from singlet-singlet energy transfer measurements between fluorescein isothiocyanate-labeled proteinases and N-(iodoacetylaminoethyl)-5-naphtylamine-1-sulfonic acid-labeled thiols in alpha 2-macroglobulin.

Binding Sites↗
PubMed1995

Subcellular localization of the low density lipoprotein receptor-related protein (alpha 2-macroglobulin receptor) in human brain.

The subcellular localization of the alpha 2-macroglobulin receptor, also known as the low density lipoprotein receptor-related protein (LRP), was studied in postmortem human brain tissue by light and electron microscopic immunocytochemistry. A specific monoclonal antibody (A2MR2) against the extracellular alpha-chain of the molecule was utilized. Light microscopically, LRP was detected strongly in neurons, weakly in some glial cells and discontinuously along capillary membranes. At the electron microscopic level, positive reaction products were found to be associated with plasma membranes, ribosomes, lysosomes and lipofuscin granules of neurons, glial cells and pericytes. The results suggest that LRP may have a function, particularly in neurons, of receptor-mediated endocytosis with subsequent lysosomal uptake and degradation of ligands such as alpha 2-macroglobulin proteinase complexes and apolipoprotein E.

Aged↗
PubMed1975

On the inhibition of elastase by serum. Some distinguishing properties of alpha1-antitrypsin and alpha2-macroglobulin.

1. The influence of serum on the elastolytic and esterolytic activity of elastase has been studied. With both substrates the inhibition curves are linear. 1 ml of normal human serum inhibits the activity of 0.77 mg of pure porcine elastase. 2. Elastase binds faster with alpha2-macroglobulin (k = 3.4-10(6) M-1 S-1) than it does with alpha1-antitrypsin (k = 5-10(5) M-1 S-1). 3. The dissociation constant of the alpha-antitrypsin -elastase complex is much lower than that of the alpha2-macroglobulin-elastase complex but both complexes are very stable (Ki less than 10(-10) M). 4. Protein pi (inter-alpha-inhibitor) does not inhibit elastase.

Animals↗
PubMed1979

Decreased sialic acid and altered binding to lectins of purified alpha 2-macroglobulin from patients with cystic fibrosis.

Purified preparations of plasma alpha 2-macroglobulin from patients with cystic fibrosis are shown to have normal amounts of total hexose but as much as 40% decrease in their sialic acid content. The binding of these preparations to concanavalin A and wheat-germ agglutinin was markedly reduced as compared to normal values in controls. Intermediate values were found in obligate heterozygotes. These results suggest a possible alteration in the carbohydrate moiety of alpha 2-macroglobulin in cystic fibrosis, presumably due to a defective posttranslational process.

Concanavalin A↗
PubMed1987

ELISA of ceruloplasmin and alpha-2-macroglobulin in paired bronchoalveolar lavage fluid and serum samples.

Bronchoalveolar lavage fluid (BALF) was analysed to obtain information on leakage of proteins from the blood into the respiratory lumen and on local synthesis. Albumin, ceruloplasmin and alpha-2-macroglobulin were measured in paired BALF and serum samples from patients with acute pneumonitis or asthma. Ceruloplasmin (CP) and alpha-2-macroglobulin (A2M) were measured by ELISAs thereby avoiding concentration of BALF. The quotients 10(3) ([protein]BALF)/(protein]serum), Qprotein, were calculated as well as the relative coefficients of excretion, RCE: Qprotein/Qalbumin. The QCP and QA2M increased parallel to Qalbumin in patients with pneumonitis and QCP increased parallel with Qalbumin in the asthma patients. This indicates that abnormal leakage of proteins from the blood rather than local synthesis cause the increased concentrations of these proteins in the BALF. Increased values for the RCE of CP and A2M were observed at normal Qalbumin. We therefore conclude that the determination of CP and A2M yields more detailed information on leakage of proteins from the blood into the airway compartment than that of albumin.

Adolescent↗