Complexes in plasma between light chain κ immunoglobulins and α1-antitrypsin respectively prealbumin

doi:10.1016/0019-2791(74)90269-9

Immunochemistry

Volume 11, Issue 11, November 1974, Pages 703-709

https://doi.org/10.1016/0019-2791(74)90269-9 Get rights and content

Abstract

Complexes between κ-chains and α₁-antitrypsin are regularly demonstrable in plasma from myeloma patients excreting more than 1 g κ-chains per litre of urine. Prealbumin produces similar complexes. These complexes are sensitive for mild reduction with thiol reagents. No corresponding complexes are produced with λ-chains. Conditions are described for the formation of the κ-α₁-antitrypsin complexes in vitro. Substitution of the terminal SH-group of the κ-chains prevents the formation of complexes as does addition of thiol reagents. A thiol-disulphide exchange seems probable between the ultimate SH-group of κ-chains and a disulphide in α₁-antitrypsin. The absence of λ-chain complexes may partly be explained by a lower reactivity of their penultimate cysteinyl than that of the terminal κ-chain thiol.

Complexes between IgA and α₁-at are regular constituents of plasma. They constitute about one per cent of the IgA. Both IgAK and IgAL produce complexes.

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Acute phase proteins constitute an essential component of the innate immune response during infection or inflammation. Human alpha-1-antitrypsin (A1AT) is one of the major acute-phase proteins found in the circulation that has originally been named for its ability to inhibit trypsin. Nonetheless, research on inhibitory functions of A1AT revealed that this protein is a major natural inhibitor of elastase, proteinase 3, and other serine proteases released from activated neutrophils. Nowadays, A1AT is viewed as a broad-spectrum inhibitor of proteases and also as a protein with antiinflammatory/immunomodulatory properties. In spite of a large amount of literature about the antiinflammatory properties ascribed to A1AT, defining the mechanisms of A1AT action remains an important priority. At least some of the pleiotropic activities of A1AT are linked to the specific molecular forms caused by oxidative modifications, nitrosylation, polymerization, cleavage, and/or interaction with other molecules.
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Citation Excerpt :
Interestingly, complexes between AAT and other proteins have been associated with specific diseases. In sera from patients with myeloma, Bence-Jones proteinemia complexes between AAT and the kappa light chain of immunoglobulins were detected.49 In plasma from diabetic subjects, complexes of AAT with factor XIa and with heat shock protein-70 (HSP70), as well as glycosylated forms of AAT were found.50,51
α1-Antitrypsin (AAT) is the archetype member of the serine protease inhibitor (SERPIN) supergene family. The AAT deficiency is most often associated with the Z mutation, which results in abnormal Z AAT folding in the endoplasmic reticulum of hepatocytes during biogenesis. This causes intra-cellular retention of the AAT protein rather than efficient secretion with consequent deficiency of circulating AAT. The reduced serum levels of AAT contribute to the development of chronic obstructive pulmonary disease (COPD) and the accumulation of abnormally folded AAT protein increases risk for liver diseases. In this review we show that with the discovery of AAT deficiency in the early 60s as a genetically determined predisposition to the development of early-onset emphysema, intensive investigations of enzymatic mechanisms that produce lung destruction in COPD were pursued. To date, the role of AAT in other than lung and liver diseases has not been extensively examined. Current findings provide new evidence that, in addition to protease inhibition, AAT expresses anti-inflammatory, immunomodulatory and antimicrobial properties, and highlight the importance of this protein in health and diseases. In this review co-occurrence of several diseases with AAT deficiency is discussed.
The reactivity and oxidation pathway of cysteine 232 in recombinant human α1-antitrypsin
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Oxidative damage to the sulfur-containing amino acids, methionine and cysteine, is a major concern in biotechnology and medicine. α1-Antitrypsin, which is a metastable and conformationally flexible protein that belongs to the serpin family of protease inhibitors, contains nine methionines and a single cysteine in its primary sequence. Although it is known that methionine oxidation in the protein active site results in a loss of biological activity, there is little specific knowledge regarding the reactivity of its unpaired thiol, Cys-232. In this study, the thiol-modifying reagent NBD-Cl (7-chloro-4-nitrobenz-2-oxa-1,3-diazole) was used to label peroxide-modified α1-antitrypsin and demonstrate that the Cys-232in vitro oxidation pathway begins with a stable sulfenic acid intermediate and is followed by the formation of sulfinic and cysteic acid in successive steps. pH-dependent reactivity with hydrogen peroxide showed that Cys-232 has a pK _a of 6.86 ± 0.05, a value that is more than 1.5 pH units lower than that of a typical protein thiol. pH-induced conformational changes in the region surrounding Cys-232 were also examined and indicate that mildly acidic conditions induce a conformation that enhances Cys-232 reactivity. In summary, this work provides new insights into α1-antitrypsin reactivity in oxidizing environments and shows that a unique structural environment renders its unpaired thiol, Cys-232, its most reactive amino acid.
Conformational properties of serine proteinase inhibitors (serpins) confer multiple pathophysiological roles
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Serine proteinase inhibitors (Serpins) are irreversible suicide inhibitors of proteases that regulate diverse physiological processes such as coagulation, fibrinolysis, complement activation, angiogenesis, apoptosis, inflammation, neoplasia and viral pathogenesis. The molecular structure and physical properties of serpins permit these proteins to adopt a number of variant conformations under physiological conditions including the native inhibitory form and several inactive, non-inhibitory forms, such as complexes with protease or other ligands, cleaved, polymerised and oxidised. Alterations of a serpin which affect its structure and/or secretion and thus reduce its functional levels may result in pathology. Serpin dysfunction has been implicated in thrombosis, emphysema, liver cirrhosis, immune hypersensitivity and mental disorders. The loss of inhibitory activity of serpins necessarily results in an imbalance between proteases and their inhibitors, but it may also have other physiological effects through the generation of abnormal concentrations of modified, non-inhibitory forms of serpins. Although these forms of inhibitory serpins are detected in tissues and fluids recovered from inflammatory sites, the important questions of which conditions result in generation of different molecular forms of serpins, what biological function these forms have, and which of them are directly linked to pathologies and/or may be useful markers for characterisation of disease states, remain to be answered. Elucidation of the biological activities of non-inhibitory forms of serpins may provide useful insights into the pathogenesis of diseases and suggest new therapeutic strategies.
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The effect of conformational changes of the α₁-proteinase inhibitor (α₁pI) on α₁PI-cholesterol complex (1:2 $mol mol$ ) formation in vitro was studied with electrophoretic and gel Chromatographic methods. Native α₁PI was modified by adding free thiol agents such as glutathione, cysteine HCl, or dl-homocysteine, by heating, or by cleavage with pancreatic elastase or trypsin. Conformational changes of the α₁PI molecule induced by these procedures were all accompanied by a loss of its ability to bind cholesterol in vitro under standard experimental conditions. The data suggest α₁PI-cholesterol binding to be affected by both direct and indirect modifications of the α₁PI-reactive center, that is situated on a mobile peptide loop.
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Complexes in plasma between light chain κ immunoglobulins and α1-antitrypsin respectively prealbumin

Abstract

Archs Biochem. Biophys.

J. biol. Chem.

Clinica Chim. Acta

Immunochemistry

Biochim. biophys. Acta

Immunochemistry

J. molec. Biol.

J. biol. Chem.

J. biol. Chem.

J. biol. Chem.

J. Immun.

Clinica. chim. Acta

Complexes in plasma between light chain κ immunoglobulins and α₁-antitrypsin respectively prealbumin