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PubMed1989

Elastase binding capacity of alpha 2-macroglobulin in plasma of patients with asthma or chronic obstructive pulmonary disease, without alpha 1-protease inhibitor deficiency.

The amidolytic activity of alpha 2-macroglobulin complexed with porcine pancreatic elastase (EC 3.4.21.11) was assayed using succinyl-trialanyl-p-nitroanilide. The levels of activity were compared in chronic obstructive pulmonary disease patients, asthma patients, and in healthy subjects with no record of lung disease. Levels of alpha 1-protease inhibitor were also determined and only those cases within the normal range for alpha 1-protease inhibitor were selected. Both the asthma cases and those with chronic obstructive pulmonary disease had levels of elastase-binding capacity related to alpha 2-macroglobulin which were significantly higher than the control groups.

Aged↗

PubMed1985

Uptake of rat and human alpha 2-macroglobulin-trypsin complexes into rat and human cells.

Uptake of rat and human alpha 2-macroglobulin-trypsin complexes was measured in rat hepatocytes, rat and human adipocytes and human fibroblasts. Uptake and degradation of 125I-labelled rat complex were about one-third of that of the human complex in the various isolated cell types. In rat hepatocytes, the apparent Km for cell association of the rat complex was about 16 nM as compared to about 6 nM for the human complex. The Vmax values were similar, about 1 X 10(4) molecules X cell-1 X min-1. Thus, rat alpha 2-macroglobulin (an acute-phase protein) complexed with trypsin follows the same pathways of uptake as the human homologue, although with a somewhat lower affinity for the uptake system.

Adipose Tissue↗

PubMed1990

A genetic polymorphism in a functional domain of human pregnancy zone protein: the bait region. Genomic structure of the bait domains of human pregnancy zone protein and alpha 2 macroglobulin.

Genomic clones containing the exons coding for the bait domain of human pregnancy zone protein and alpha 2 macroglobulin were isolated and fragments containing the bait exons were sequenced. It is shown that the bait domains of both alpha 2 macroglobulin and pregnancy zone protein are encoded by two exons, with conserved exon/intron boundaries. A genetic polymorphism showing either a Met or a Val residue as the sixth amino acid of the pregnancy zone protein bait domain was detected with the rare Met allele showing a gene frequency of 0.065.

Amino Acid Sequence↗

PubMed1990

Evidence that the newly cloned low-density-lipoprotein receptor related protein (LRP) is the alpha 2-macroglobulin receptor.

The human placental receptor (alpha 2MR) for alpha 2-macroglobulin-proteinase complexes contains 3 polypeptides of approx. 500 kDa, 85 kDa, and 40 kDa. N-terminal sequence analysis of the 500 kDa and 85 kDa polypeptides, analysis of a random selection of peptides convering 536 residues from these polypeptides, and analysis of a 1772 bp cDNA encoding part of the 500 kDa polypeptide provide evidence that the 500 kDa and 85 kDa chains are the alpha- and beta-subunits, respectively, of a recently cloned hepatic membrane protein, termed the low density lipoprotein receptor related protein (LRP) (Herz, J., Hamann, U., Rogne, S., Myklebost, O., Gausepohl, H. and Stanley, K.K. (1988) EMBO J. 7, 4119-4127; Herz, J., Kowal, R.C., Goldstein, J.L. and Brown, M.S. (1990) EMBO J. 9, 1769-1776). N-terminal sequence analysis of the 40 kDa polypeptide shows that it is of distinct genetic origin. It is suggested that LRP is the functional receptor for alpha 2-macroglobulin-proteinase complexes (alpha 2MR) and in addition may have as yet unsettled functions in lipoprotein metabolism.

Amino Acid Sequence↗

PubMed1991

Alpha 2-macroglobulin synthesis in interleukin-6-stimulated human neuronal (SH-SY5Y neuroblastoma) cells. Potential significance for the processing of Alzheimer beta-amyloid precursor protein.

Cultured human neuronal (SH-SY5Y neuroblastoma) cells synthesize and secrete the potent protease inhibitor alpha 2-macroglobulin (a2M) upon stimulation with interleukin-6 (IL-6) indicating that alpha 2-macroglobulin behaves as an acute-phase protein in the human central nervous system. Exogenous addition of a2M to the cultured neuronal cells resulted in only a slight inhibition of Alzheimer beta A4-amyloid precursor protein (APP) synthesis, but markedly inhibited its secretion pointing to the possibility that a2M may affect the proteolytic APP processing. Evidence is provided that IL-6 and a2M are involved in Alzheimer's disease pathogenesis.

Alzheimer Disease↗

PubMed1993

Isolation, characterization and partial sequencing of Pregnancy Associated Mouse Protein PAMP1 identifies it as a novel female specific protein, unrelated to the alpha-2-macroglobulin family of proteinase inhibitors.

Pregnancy Associated Mouse Protein 1 (PAMP1) was isolated from plasma of female mice. An antiserum raised against the purified protein confirmed its immunochemical identity with the originally described PAMP1. Pregnant females were observed to have plasma levels of PAMP1 that are increased two-fold at day 10-13 of gestation relative to non-pregnant females, while male mouse plasma did not contain PAMP1. The purified protein displayed an apparent subunit molecular mass of 70 kDa, irrespective of cystine reduction. The native molecular mass, estimated by gel-filtration, was about 140 kDa, indicating that PAMP1 is circulating as a non-covalent homodimer. The amino-terminal sequence of the intact protein and the internal sequences of four cyanogen bromide fragments demonstrated that this protein is not related to any known member of the alpha-2-macroglobulin family nor to any protein in the sequence databases. The physicochemical and the sequence data thus establish this protein as a novel, female-specific protein, but unrelated to the Macroglobulin proteinase inhibitor family.

Amino Acid Sequence↗

PubMed1995

The effect of residue 1106 on the thioester-mediated covalent binding reaction of human complement protein C4 and the monomeric rat alpha-macroglobulin alpha 1 I3.

The histidine at position 1106 of the C4B isotype of human complement is involved in catalyzing the covalent binding of the thioester to glycerol and water. By replacing the histidine with other residues, it was found that tyrosine is also capable of mediating the reaction. We propose that they act as nucleophiles by first attacking the thioester, upon activation, to form acyl intermediates, which subsequently react with the hydroxyl groups of glycerol or water. The monomeric alpha-macroglobulin, alpha 1I3 of the rat, was also studied. Unlike alpha 2-macroglobulin, which is a tetramer, alpha 1I3 has binding properties similar to those of C4A.

Amino Acid Sequence↗

PubMed1983

Isolation and characterization of horse alpha 2-macroglobulin protease inhibitor.

Several publications have described in the past properties of partly purified horse alpha 2-macroglobulin (alpha 2M) which are strikingly different from the human alpha 2M. Horse alpha 2M was therefore isolated to purity by classical procedures, i.e. affinity chromatography, ion exchange chromatography and gel filtration, and its properties are compared with those of its human counterpart. The molecular weight of the native protein and its subunits, the isoelectrofocusing pattern and the change in electrophoretic mobility caused by interaction with protease were similar to those of human alpha 2M. Horse alpha 2M had a broad enzyme specificity and inhibited enzymatic action on macromolecules but not on small molecular weight synthetic substrates. In addition the horse and human alpha 2M were found to be immunochemically related when examined by specific antisera to human as well as to horse alpha 2-macroglobulin.

Animals↗

PubMed1979

Soluble proteins in the human atherosclerotic plaque. With spectral reference to immunoglobulins, C3-complement component, alpha 1-antitrypsin and alpha 2-macroglobulin.

A number of soluble proteins contained in human aortic intimal tissue was extracted into buffered saline (pH 7.4) and identified and quantitated by immunoelectrophoresis and immunodiffusion. The proteins included IgA, IgG, IgM, B1C (C3), alpha 1-antitrypsin, alpha 2-macroglobulin, fibrinogen, albumin, LDL, HDL, alpha 1-acid glycoprotein, beta 2-glycoprotein, transferrin and ceruloplasmin. The concentration of soluble proteins was significantly higher in the atherosclerotic intima than in the normal intima. The diseased intima also contained a small amount of tissue-bound IgG, IgA and B1C which was extractable with citrate buffer at pH 3.2. The vascular band IgG, and B1C were shown by enzymatic and immunohistochemical studies to be closely associated with the collagenous tissue of the plaque. The Ig contained in the atherosclerotic plaque may be derived in part from the biosynthesis of Ig by the artery, since the incorporation of 14C-labeled leucine into IgG by the atheromatous plaque was demonstrable by radioimmunoelectrophoresis. In contrast to the diseased artery, the normal artery did not synthesize IgG and did not contain vascular bound IgG or complement. However, the normal artery was capable of fixing IgG and B1C eluted from the diseased artery. The present studies suggested that the IgG contained and synthesized by the plaque might represent an immune response to an endogenous or exogenous antigen closely associated with plaque collagen. IgG and B1C either alone or in the form of an immune complex also may play an important role in phagocytosis in the plaque and thereby influence the course of atherosclerosis. The proteolytic inhibitors, alpha 1-antitrypsin and alpha 2-macroglobulin, found in relatively high concentrations in the plaque, could enhance fibrosis of the lesion because of thier known inhibitory effects on collagenase and elastase.

Aorta↗

PubMed1994

Use of hydrophobic affinity partitioning as a method for studying various conformational states of the human alpha-macroglobulins.

The serum proteins alpha 2-macroglobulin and pregnancy zone protein undergo major conformational changes when complexed with proteinases. It is shown that the changes in delta log Kmax determined by hydrophobic affinity partitioning is a measure of the extent of changes in the conformation of these alpha-macroglobulins. We introduce a new term for the changes of surface hydrophobicity in a protein as delta log Kacc. This defines the difference of delta log Kmax between a modified and an unmodified conformational state of a specific protein and can be useful as a parameter to describe the apparent conformational changes in the protein.

Centrifugation↗

PubMed1979

Agarose isoelectric focusing of native human immunoglobulin M and alpha 2-macroglobulin.

The resolution of native 19S IgM and alpha 2-macroglobulin by agarose isoelectric focusing is described. The agarose used was practically charge free, thus avoiding disadvantages of electroendoosmosis, and gives a very large network gel, with minimal molecular sieving effects. The resolving power is comparable to that obtained in thin-layer isoelectric focusing in polyacrylamide gel. Clones of human IgM showed a microclonal heterogeneity, similar to IgG antibody heterogeneity, alpha 2-macroglobulin gave a pattern of seven bands in the pI range of 4.1 to 4.9. The flexibility of the agarose isoelectric focusing (IEF) system with regard to immunodetection techniques is illustrated by the use of immunofixation and two-dimensional crossed immunoelectrofocusing. The agarose IEF method has several advantages, viz., non-toxicity, simple handling, uniform and rapid gel formation, and considerably shortened fixing and staining times. The value of the new method is discussed, in particular its usefulness in detecting and isolating IgM antibodies of known specificity produced by cells in culture.

Humans↗

PubMed1983

Detection of Candida proteinase by enzyme immunoassay and interaction of the enzyme with alpha-2-macroglobulin.

Double antibody immunoassay of secretory aspartic proteinases from 2 strains of the yeast Candida albicans was performed in microtest plates with rabbit antibody and peroxidase conjugated rabbit antibody. The test detects approximately 0.1 ng of proteinase and is 2 orders of magnitude more sensitive than direct measurement of enzymic activity with hemoglobin as a substrate. The immunoassay was affected both by alkaline denaturation, which is a common feature of aspartic proteinases, and by the presence of the proteinase scavenger alpha-2-macroglobulin. Conditions are described that allow for comparison of proteinases from different strains of yeast and minimize the interference of macroglobulin.

Animals↗

PubMed1994

A simple method for isolating alpha 2 macroglobulin-cytokine complexes.

There is the need for a simple, effective procedure for separating alpha 2 macroglobulin-cytokine complexes from free cytokine in order that the nature and possible immunological significance of cytokine-binding by alpha 2 macroglobulin (alpha 2-M) might be further investigated. This presentation describes a method which exploits the presence of zinc-binding sites on alpha 2-M which permit the isolation of complexes from other proteins by zinc-affinity chromatography. Furthermore the method may be used in either a column or batch format.

Chromatography, Affinity↗

PubMed1993

Laser nephelometric evaluation of albumin, IgG and alpha 2-macroglobulin: applications to the study of alterations of the blood-brain barrier.

Cerebrospinal fluid and serum levels of albumin, immunoglobulin G and alpha 2-macroglobulin were determined by laser nephelometer in various pathological conditions: Guillain-Barré syndrome amyotrophic lateral sclerosis, lumbar disc herniation. These proteins are different due to their molecular weight, spacial conformation, CSF and serum concentrations and their CSF/serum quotient reflects the status of the blood-brain barrier. In the subjects group comparisons, albumin quotient and IgG quotient show a significant differentiations. The linear regression of albumin quotient compared to alpha 2-macroglobulin quotient behaves differently in the individual groups. The protein CSF/serum quotients are helpful in distinguishing the causes of alterations in the blood-brain barrier.

Adolescent↗

PubMed1986

Interaction of SK-human plasmin, SK-dog plasmin complexes with alpha 2-antiplasmin and alpha 2-macroglobulin.

In patients treated with streptokinase there is a rapid and significant decrease in the level of fibrinogen in the circulation. In dogs given streptokinase there is no such change in circulating fibrinogen. To find an explanation for this species difference in response to streptokinase, the inhibition of SK-human plasmin and SK-dog plasmin by soybean trypsin inhibitor, alpha 2-antiplasmin and alpha2-macroglobulin were compared in this study. Soybean trypsin inhibitor completely blocked the hydrolysis of S-2251 substrate (D-val-L-leu-lys-p-nitroanilide) by SK-dog plasmin and had no effect on SK-human plasmin. Alpha 2-Antiplasmin, the physiologically important regulator of fibrinolysis, inhibited S-2251 hydrolysis by SK-dog plasmin but not the activity of SK-human plasmin. alpha 2-Macroglobulin showed 100% inhibition of proteolytic activity and 50% inhibition of S-2251 activity of SK-dog plasmin, and had no effect on SK-human plasmin. Studies with fresh human and dog plasma also showed that the SK-dog plasmin is rapidly inactivated by the alpha 2-antiplasmin present in the plasma. The inactivation of SK-dog plasmin and not SK-human plasmin by plasma inhibitors explains the differences in the response of dog and humans to the administration of streptokinase.

Animals↗

PubMed1985

Antigenic determinants of pregnancy-associated alpha 2-glycoprotein and alpha 2-macroglobulin defined by poly- and monoclonal antibodies.

Human alpha 2-macroglobulin and pregnancy-associated alpha 2-glycoprotein (PA alpha 2G) share several physicochemical characteristics. By the use of unabsorbed or absorbed polyclonal antibodies to these antigens, the existence of common epitopes in these molecules were demonstrated in crossed immunoelectrophoresis. Two monoclonal antibodies out of 9 raised against purified PA alpha 2G were demonstrated to react with both antigens, indicating close immunochemical relatedness between these macroglobulins. The findings might have functional implications.

Animals↗

PubMed1989

Covalent binding to alpha-macroglobulins of a protein with free SH groups produced by activated B cells: blocking by D-penicillamine and gold compounds.

alpha 2-Macroglobulin (alpha 2M) complexed with proteinases or modified by the action of amines has been shown to affect immune responses in vitro, though as yet the mechanisms are poorly understood. Supernates from rabbit lymphoid cells cultured in medium with normal rabbit serum and 35S-methionine (or 14C-leucine) were found to contain intensely radiolabeled alpha-macroglobulins (alpha M) (alpha 1 and alpha 2) on electrophoresis. When human alpha 2 M, instead of rabbit serum, was added to cultures, it also appeared radiolabeled, suggesting that lymphocyte-produced proteins (LyP) formed complexes with serum alpha M. These alpha M-associated LyP were produced in greater quantity when lymphocytes were cultured in the presence of mitogens; they were not produced by cells cultured in the presence of cycloheximide; they were produced primarily by B cells rather than T cells or macrophages. Pretreatment of serum or alpha M with methylamine, enhanced rather than inhibited the formation of LyP-alpha M complexes, a finding which is contrary to that expected if the LyP were a proteinase. Since this methylamine treatment of alpha M also results in the generation of free SH groups from the internal thioester bonds of alpha M, the formation of disulfide bonds between LyP and alpha M was considered. Indeed, (a) the LyP-alpha M complex formation was inhibited by N-ethylmaleimide, aurothiomalate, sodium aurothioglucose or D-penicillamine; (b) blocking the SH groups with NEM, of either culture fluid supernates or serum, had an inhibitory effect on the formation of these complexes; (c) the LyP-alpha M complexes were dissociated by sodium dodecyl sulfate (SDS) only after their reduction with 2-mercaptoethanol (2-ME). Thus, a disulfide bond was formed between alpha M and LyP with free SH groups (SH-LyP). Molecular sieving by high performance liquid chromatography (HPLC) of the serum-free radiolabeled supernates indicated that SH-LyP eluted at a position corresponding to a polypeptide of mol. wt of about 22,000. However, SDS-PAGE of the 22,000 mol. wt HPLC fraction showed that the major protein was approximately mol. wt 11,000 under both reducing and non-reducing conditions. In addition, the SH-LyP reduced by 2-ME from its binding site on alpha 2M had a mol. wt of about 11,000 in SDS-PAGE, suggesting that it was a non-covalent homodimer of mol. wt 11,000 polypeptides. We suggest that alpha 2M as well as SH-LyP may affect the immune system by functioning as SH-reactive agents.

Animals↗

PubMed1985

The plasma clearance of human alpha 2-macroglobulin-trypsin complex in the rat is mainly accounted for by uptake into hepatocytes.

Rats were given intravenous injections of 125I-labelled human alpha 2-macroglobulin X trypsin. The half-time of disappearance of radioactivity from arterial blood was 2 min. External counting showed that radioactivity in the liver was maximal by 10 min and then decreased slowly. 87% of the injected dose was recovered in the liver by 10 min. Light- and electron microscopic autoradiography carried out on samples of liver fixed with glutaraldehyde 3 min or 30 min after the injection showed that 85-90% of the grains were over the hepatocytes and 4-9% were over the Kupffer cells. Thus, uptake into hepatocytes, and not into Kupffer cells as believed previously, appears to account for the major part of the uptake of alpha 2-macroglobulin X trypsin by the liver and thereby for its rapid removal from the blood.

Animals↗