Identification of hydrophobic fragments of α<sub>1</sub>‐antitrypsin and Cl protease inhibitor in human bile, plasma and spleen

Johansson, Jan; Gröndal, Staffan; Sjövall, Jan; Jörnvall, Hans; Curstedt, Tore

doi:10.1016/0014-5793(92)80234-8

Cited by 40 publications

(24 citation statements)

References 25 publications

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“…These two hydrophobic proteins constitute about 1% of the total surfactant mass [74]. Direct attempts to purify SP-B and/or SP-C or related polypeptides from extrapulmonary sources were unsuccessful [75]. In transgenic mice, using SP-C/diphtheria toxin A or SP-C/chloramphenicol acetyltransferase gene hybrids, SP-C was found not to be expressed in any other major organ than the lung [76,77], indicating that at least this surfactant protein is lung-specific.…”

Section: Composition Of Surfactantmentioning

confidence: 99%

The proteins of the surfactant system

Johansson¹,

Curstedt²,

Robertson³

1994

Eur Respir J

204

143

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T Th he e p pr ro ot te ei in ns s o of f t th he e s su ur rf fa ac ct ta an nt t s sy ys st te em m SP-B is a 79-residue polypeptide that contains three intrachain disulphide bridges. It exists mainly as a homodimer, which is strongly positively charged and may selectively remove anionic and unsaturated lipid species from the alveolar surface film, thereby increasing surface pressure.SP-C is a mainly α-helical, extraordinarily hydrophobic polypeptide containing 35 amino acid residues and covalently linked palmitoyl groups. Its α-helical portion is inserted into surfactant lipid bilayers. SP-C accelerates the adsorption of lipid bilayers to an interfacial monolayer. In babies with respiratory distress syndrome, the clinical response to treatment with surfactant containing SP-B and SP-C is much faster than in babies treated with protein-free synthetic surfactant.We speculate that, in the near future, surfactant preparations based on recombinant hydrophobic proteins will be available for clinical use.

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Section: Composition Of Surfactantmentioning

confidence: 99%

The proteins of the surfactant system

Johansson¹,

Curstedt²,

Robertson³

1994

Eur Respir J

204

143

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“…8,9 The resulting 4-kDa carboxy-terminal fragment of 36 residues (C-36) still binds the complex noncovalently, but under denaturing conditions in vitro, the C-36 fragment dissociates from the complex. 10,11 Recent studies have elucidated the biological activities of the C-36 fragment: upregulation of expression of the LDL receptor in HepG2 cells [12][13][14] and induction of cytokine production and CD36 expression in monocytes. 15 Furthermore, it is involved in neutrophil recruitment.…”

mentioning

confidence: 99%

In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL

Mashiba

Wada

Takeya

et al. 2001

ATVB

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Abstract-An inactivated form of ␣ 1 -antitrypsin (AT) and LDL coelutes in gel permeation chromatography. To characterize and to quantify the amount of this fraction of AT, a monoclonal antibody was established against chloramine T-oxidized AT and named OxAT-4. OxAT-4 recognized the oxidatively modified AT, including hexylaldehyde-or 4-hydroxy-2-nonenal-modified AT, but neither normal active AT nor trypsin/AT complex. Comigration of apoB and oxidized AT was demonstrated by Western blotting analysis of AT-LDL by means of anti-apoB monoclonal antibody and OxAT-4. A complex of oxidized AT and LDL (AT-LDL) was isolated from human plasma LDL by affinity column with an OxAT-4 antibody-coated carrier. AT-LDL was degraded 4 times more effectively by mouse peritoneal macrophages, but this was not mediated by scavenger receptor class A type I. Localization of AT-LDL was detected in human atherosclerotic lesions of the coronary artery, but distribution of it was not completely identical to that of macrophages. In situ hybridization revealed AT expression by macrophages, which were present in intimal layers of the coronary artery. From these findings, we concluded that AT is produced and oxidized by macrophages, then attached to LDL in the intimal layer of the arterial wall. Although AT-LDL that escapes into the blood stream can be cleared by hepatocytes, the remaining AT-LDL may be taken up by macrophages and contribute to the lipid accumulation in arterial wall cells as the early stage of atherogenesis. Key Words:erine proteinase activity is regulated by a group of inhibitors of the serine proteinases (also called serpin). ␣ 1 -Antitrypsin (AT) is one of the serpin family proteins. It is produced mainly in the liver, and partly by macrophages stimulated by interleukin-6 or lipopolysaccharide. 1-5 At inflammatory sites, AT protects the tissue against damage caused by proteinases derived from white blood cells; in the lung, AT is produced by monocytes, which are stimulated by endotoxin, interleukin-1, and tumor necrosis factor-␣ and protect the alveolar microstructure against excess activity of proteinases. 6,7 After formation of complexes of AT with serine proteinase, AT is cleaved at the site of the serpin reactive loop and changed into the inactive form. 8,9 The resulting 4-kDa carboxy-terminal fragment of 36 residues (C-36) still binds the complex noncovalently, but under denaturing conditions in vitro, the C-36 fragment dissociates from the complex. 10,11 Recent studies have elucidated the biological activities of the C-36 fragment: upregulation of expression of the LDL receptor in HepG2 cells [12][13][14] and induction of cytokine production and CD36 expression in monocytes. 15 Furthermore, it is involved in neutrophil recruitment. 16,17 Thus, not only AT itself but also the byproducts of its enzymatic inhibition possess biological activities at the locus of inflammation.Oxidized AT is another modified form of ␣ 1 -AT, which is found in inflammatory exudates at levels of Ϸ5% to 10% of total AT 18,19 and inflammatory sy...

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“…Indirect evidence has suggested that interaction with ai-proteinase inhibitor takes place through binding with the hydrophobic domain C terminal to the reactive center of the serpin. This 36-amino acid peptide has recently been isolated from human tissues, such as bile, blood, and spleen (11). The closely related serpin ACT possesses a homologous, hydrophobic C-terminal domain (12), which may be expected to interact in a similar fashion.…”

mentioning

confidence: 99%

Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

Eriksson

Janciauskiene

Lannfelt

1995

Proc. Natl. Acad. Sci. U.S.A.

139

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The major component of the cerebral plaques in Alzheimer disease is the j3-amyloid peptide, but serine proteinase inhibitors like cvl-antichymotrypsin (ACT) are also present. Their role in the pathogenesis of amyloid formation is unsettled. In addition to their function as proteinase inhibitors, serine proteinase inhibitors can interact with various hydrophobic compounds, a reaction accompanied by a transition from the stressed to the relaxed conformation. We report here on the ability of ACT to regulate the formation of j3-amyloid fibrils in vitro. In a molar ratio of 1:10 (ACT to f8-amyloid) ACT inhibits ,3-amyloid fibril formation. Furthermore, ACT promotes rapid disaggregation of f8-amyloid fibrils when added in the same molar ratio to preformed ,8-amyloid fibrils. These processes are accompanied by increased thermostability of ACT and loss of its biological activity, consistent with a conformational transition of ACT from the stressed to the relaxed state. The influence of ACT on f3-amyloid fibril formation may be an example of a hydrophobic interaction between the j3-amyloid peptide and the hydrophobic domain C terminal to the reactive center of ACT.Alzheimer disease (AD) is a neurodegenerative disorder characterized by abnormal deposition of extracellular congophilic plaques in the brain (1). The main constituent of senile plaques is a 39-to 43-amino acid peptide, called 13-amyloid, which is a proteolytic fragment of the amyloid precursor protein (2). The metabolism of amyloid precursor protein is only partially understood. The proteases responsible for amyloid precursor protein processing and the sites in the brain where these proteolytic events occur are unknown (3). Recently, it was demonstrated that ,B-amyloid is a product of normal cellular metabolism (4-6). Different lengths of the peptide exist, but the major form is 40-42 amino acids, which in solution exist in a monomeric a-helical conformation. In vitro studies have shown that changes in pH, concentration, and temperature result in conformational rearrangements from an a-helix to an oligomeric 13-sheet, which precipitates from solution and produces amyloid-like deposits (7). f3-Amyloid is thought to be important early in the pathogenesis of AD (L.L., unpublished data).Serine proteases and their inhibitors like a1-antichymotrypsin (ACT) and ai-proteinase inhibitor have been identified in different types of amyloid fibril isolates (8). The presence of these proteins in the extracellular amyloid deposits suggests a number of potential roles they may play in the pathogenesis of AD. Recently, it has been shown that a specific sequence within the N-terminal 10 amino acid residues of the f3-amyloid peptide is responsible for the formation of an ACT-amyloid complex (9). These authors also noted that ACT induced fibril disaggregation in vitro. The increased expression of ACT by astrocytes in areas of Alzheimer lesions in the brain known to have many neuritic plaques support such a role (9).Understanding how a normally soluble protein is transform...

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Identification of hydrophobic fragments of α₁‐antitrypsin and Cl protease inhibitor in human bile, plasma and spleen

Cited by 40 publications

References 25 publications

The proteins of the surfactant system

The proteins of the surfactant system

In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL

Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

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Identification of hydrophobic fragments of α1‐antitrypsin and Cl protease inhibitor in human bile, plasma and spleen

Cited by 40 publications

References 25 publications

The proteins of the surfactant system

The proteins of the surfactant system

In Vivo Complex Formation of Oxidized α 1 -Antitrypsin and LDL

Alpha 1-antichymotrypsin regulates Alzheimer beta-amyloid peptide fibril formation.

Contact Info

Product

Resources

About

Identification of hydrophobic fragments of α₁‐antitrypsin and Cl protease inhibitor in human bile, plasma and spleen

In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL