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PubMed1989

Models for the C1 complex determined by physical techniques.

The C1 complex is an association of C1q and C1r2C1s2. Neutron scattering and ultracentrifugation provide a valuable means of understanding the solution structure of the subcomponents and their complex, and these can be supplemented by protein structure prediction techniques. C1q is constructed from six globular heads connected by collagen-like arms. The solution data for C1q show that the arms are of length 14.5 nm and not 11.5 nm as proposed from electron microscopy, the average arm-axis angle is 40 degrees, and that the structure is flexible in solution at the junction of the six arms. The sequences of C1r and C1s show that each is constructed from six protein domains. C1r and C1s are elongated macromolecules of lengths 18-20 nm. Their solution properties are best described as the lengthwise arrangement of a protease domain of diameter 4 nm, two "short consensus repeat" domains, each of length 4 nm, and an N-terminal globular entity of length 6 nm containing the first three protein domains. Solution data on the C1r2 dimer is interpreted as an X-shaped association of the two C1r monomers as proposed from electron microscopy. Six criteria are enumerated for constructing models of C1 from these two structures, and four distinct models for the C1 complex are reviewed. While further evidence is required to make this choice unequivocal, the W-model is favoured. This places each monomer of C1r and C1s on four adjacent arms of C1q, and offers the most reasonable explanation of the known properties of the C1 complex.

Complement C1↗
PubMed1989

The structures of human C1r and C1s and their relationship to other serine proteases.

The recent sequencing of the C1 subcomponents has allowed comparison with other molecules of homologous primary structure. Where tertiary structures are available for at least one member of the family it is possible to make further progress by modelling the amino acid sequence of the complement protein into the three-dimensional coordinates of the directly determined structure, thereby obtaining an approximation of the structure of the complement protein. Molecular modelling allows structure-function relationships to be explored and suggests further experiments that may be amenable to techniques such as site-directed mutagenesis.

Amino Acid Sequence↗
PubMed1999

The N-terminal CUB-epidermal growth factor module pair of human complement protease C1r binds Ca2+ with high affinity and mediates Ca2+-dependent interaction with C1s.

The Ca2+-dependent interaction between complement serine proteases C1r and C1s is mediated by their alpha regions, encompassing the major part of their N-terminal CUB-EGF-CUB (where EGF is epidermal growth factor) module array. In order to define the boundaries of the C1r domain(s) responsible for Ca2+ binding and Ca2+-dependent interaction with C1s and to assess the contribution of individual modules to these functions, the CUB, EGF, and CUB-EGF fragments were expressed in eucaryotic systems or synthesized chemically. Gel filtration studies, as well as measurements of intrinsic Tyr fluorescence, provided evidence that the CUB-EGF pair adopts a more compact conformation in the presence of Ca2+. Ca2+-dependent interaction of intact C1r with C1s was studied using surface plasmon resonance spectroscopy, yielding KD values of 10.9-29.7 nM. The C1r CUB-EGF pair bound immobilized C1s with a higher KD (1.5-1.8 microM), which decreased to 31.4 nM when CUB-EGF was used as the immobilized ligand and C1s was free. Half-maximal binding was obtained at comparable Ca2+ concentrations ranging from 5 microM with intact C1r to 10-16 microM for C1ralpha and CUB-EGF. The isolated CUB and EGF fragments or a CUB + EGF mixture did not bind C1s. These data demonstrate that the C1r CUB-EGF module pair (residues 1-175) is the minimal segment required for high affinity Ca2+ binding and Ca2+-dependent interaction with C1s and indicate that Ca2+ binding induces a more compact folding of the CUB-EGF pair.

Animals↗
PubMed1988

A common neoepitope is created when the reactive center of C1-inhibitor is cleaved by plasma kallikrein, activated factor XII fragment, C1 esterase, or neutrophil elastase.

The reactive center of C1-inhibitor, a plasma protease inhibitor that belongs to the serpin superfamily, is located on a peptide loop which is highly susceptible to proteolytic cleavage. With plasma kallikrein, C1s and beta-Factor XIIa, this cleavage occurs at the reactive site residue P1 (Arg444); with neutrophil elastase, it takes place near P1, probably at residue P3 (Val442). After these cleavages, C1-inhibitor is inactivated and its conformation is modified. Moreover, in vivo, cleaved C1-inhibitor is removed from the blood stream more rapidly than the intact serpin, which suggests that proteolysis unmasks sites responsible for cellular recognition and the uptake of the cleaved inhibitor. In the study reported here, we show, using an MAb, that an identical neoepitope is created on C1-inhibitor after the cleavage of its exposed loop by plasma kallikrein, C1s, beta-Factor XIIa, and by neutrophil elastase.

Animals↗
PubMed2001

Proteinase inhibitors from the medicinal leech Hirudo medicinalis.

The medicinal leech Hirudo medicinalis produces various types of proteinase inhibitors: bdellins (inhibitors of trypsin, plasmin, and acrosin), hirustasin (inhibitor of tissue kallikrein, trypsin, alpha-chymotrypsin, and granulocyte cathepsin G), tryptase inhibitor, eglins (inhibitors of alpha-chymotrypsin, subtilisin, and chymasin and the granulocyte proteinases elastase and cathepsin G), inhibitor of factor Xa, hirudin (thrombin inhibitor), inhibitor of carboxypeptidase, and inhibitor of complement component C1s. This review summarizes data on their primary and tertiary structures, action mechanisms, and biological activities.

Animals↗
PubMed1979

Multiple effects of a diamidine (propamidine) on complement activation.

Propamidine, one of the diamidines used against infections with babesiae has inhibitory and enhancing effects on complement activation as assessed by immune haemolysis of sensitized sheep red cells. Utilization of C1 is powerfully, that of C3 weakly improved by propamidine while activation and/or fixation of C4, C5 and to a lesser degree of C8 and C9 are inhibited. At low concentrations of propamidine (less than 2 mM) the enhancing effects, at higher concentrations the inhibitory effects predominate. Inhibition is produced, in some cases certainly, in others likely, by interference of propamidine with binding properties of complement components. None of the complement enzymes, C1s, C42 or C3bBb was inhibited in its hydrolytic activity. The possible significance of propamidine actions is discussed.

Amidines↗
PubMed2001

Impact of inhibition of complement by sCR1 on hepatic microcirculation after warm ischemia.

Recent observations provide evidence that complement is implicated as an important factor in the pathophysiology of ischemia/reperfusion injury (IRI). Here, we assessed the effects of complement inhibition on hepatic microcirculation by in vivo microscopy (IVM) using a rat model of warm hepatic ischemia clamping the left pedicle for 70 min. Ten animals received the physiological complement regulator soluble complement receptor type 1 (sCR1) intravenously 1 min prior to reperfusion. Controls were given an equal amount of Ringer's solution (n = 10). Microvascular perfusion and leukocyte adhesion were studied 30 to 100 min after reperfusion by IVM. Microvascular perfusion in hepatic sinusoids was significantly improved in the sCR1 group (80.6 +/- 0.6% of all observed sinusoids were perfused [sCR1] vs 67.3 +/- 1.2% [controls]). The number of adherent leukocytes was reduced in sinusoids (49.9 +/- 3.4 [sCR1] vs 312.3 +/- 14.2 in controls [adherent leukocytes per square millimeter of liver surface]; P < 0.001) as well as in postsinusoidal venules after sCR1 treatment (230.9 +/- 21.7 [sCR1] vs 1906.5 +/- 93.5 [controls] [adherent leukocytes per square millimeter of endothelial surface]; P < 0.001). Reflecting reduced hepatocyte injury, liver transaminases were decreased significantly upon sCR1 treatment compared to controls. Our results provide further evidence that complement plays a decisive role in warm hepatic IRI. Therefore, we conclude that complement inhibition by sCR1 is effective as a therapeutical approach to reduce microcirculatory disorders after reperfusion following warm organ ischemia.

Animals↗
PubMed2001

Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and -2, MBL-associated protein 19, and MBL.

The mannan-binding lectin (MBL) activation pathway of complement plays an important role in the innate immune defense against pathogenic microorganisms. In human serum, two MBL-associated serine proteases (MASP-1, MASP-2) and MBL-associated protein 19 (MAp19) were found to be associated with MBL. With a view to investigate the interaction properties of these proteins, human MASP-1, MASP-2, MAp19, as well as the N-terminal complement subcomponents C1r/C1s, Uegf, and bone morphogenetic protein-1-epidermal growth factor (CUB-EGF) segments of MASP-1 and MASP-2, were expressed in insect or human kidney cells, and MBL was isolated from human serum. Sedimentation velocity analysis indicated that the MASP-1 and MASP-2 CUB-EGF segments and the homologous protein MAp19 all behaved as homodimers (2.8-3.2 S) in the presence of Ca(2+). Although the latter two dimers were not dissociated by EDTA, their physical properties were affected. In contrast, the MASP-1 CUB-EGF homodimer was not sensitive to EDTA. The three proteins and full-length MASP-1 and MASP-2 showed no interaction with each other as judged by gel filtration and surface plasmon resonance spectroscopy. Using the latter technique, MASP-1, MASP-2, their CUB-EGF segments, and MAp19 were each shown to bind to immobilized MBL, with K:(D) values of 0.8 nM (MASP-2), 1.4 nM (MASP-1), 13.0 nM (MAp19 and MASP-2 CUB-EGF), and 25.7 nM (MASP-1 CUB-EGF). The binding was Ca(2+)-dependent and fully sensitive to EDTA in all cases. These data indicate that MASP-1, MASP-2, and MAp19 each associate as homodimers, and individually form Ca(2+)-dependent complexes with MBL through the CUB-EGF pair of each protein. This suggests that distinct MBL/MASP complexes may be involved in the activation or regulation of the MBL pathway.

Amino Acid Motifs↗
PubMed1997

Role of the distal hinge region of C1-inhibitor in the regulation of C1s activity.

A synthetic peptide corresponding to residues 448-459 of C1-inhibitor (C1-inh) binds to C1s, is a non-competitive inhibitor of C1s activity and prevents formation of an SDS-stable C1s-C1-inh complex. Substitutions of residues Q452, Q453 or F455 in this peptide resulted in loss of C1s binding and inhibitory activity of the peptide. NMR analysis of the peptide showed an area of well-defined structure from E450 to F455. The side chains of Q452, Q453 and Q455 were exposed to the solvent and therefore available for C1s binding. The defined structure in the peptide is compatible with our computer model of the serpin domain of C1-inh.

Complement C1 Inactivator Proteins↗
PubMed1993

Regulation of the synthesis of C1 subcomponents and C1-inhibitor.

We have investigated the synthesis of C1q, C1r, C1s and C1-inhibitor in HepG2 cells, human umbilical vein endothelial cells (HUVEC), fibroblasts (skin and synovial membrane), chondrocytes and monocytes. C1q was only synthesised by monocytes, although the mRNAs for the C1qA and C1qC chains were expressed in HUVEC. C1r, C1s and C1-inhibitor were synthesised by all cell types. The secretion rates of C1r and C1s were approximately equimolar in fibroblasts and chondrocytes whereas the secretion rate for C1s exceeded that for C1r in the other cell types. Molar ratios of C1s to C1r were approximately 2:1 for HepG2 cells, 5:1 for monocytes and 10:1 for HUVEC. Stimulation with interferon-gamma resulted in increased expression of all four proteins. The C1s:C1r ratio did not alter in chondrocytes or fibroblasts, but approached unity in HepG2, monocytes and HUVEC, due to relatively greater stimulation of C1r gene expression.

Carcinoma, Hepatocellular↗
PubMed1985

Characterization of C1q, C1s and C-1 Inh synthesized by stimulated human monocytes in vitro.

C1q, C1s and C1 Inh synthesized and secreted by human monocytes were characterized by SDS-PAGE. C1q is formed of three chains A (Mr approximately 35 000), B (Mr approximately 33 000) and C (Mr approximately 25 000) which are associated in two subunits A-B and C-C. It appears identical to C1q purified from plasma. C1s is secreted as a non-activated, monocatenar protein of Mr approximately 87 000 identical to proenzymic C1s from plasma. Secreted C1 Inh (Mr approximately 100 000) has a slightly higher Mr than purified plasmatic C1 Inh. Monensin treatment of the cells favours the intracytoplasmic accumulation of products at various glycosylation stages.

Cells, Cultured↗
PubMed1989

Biosynthesis of C1r and C1s subcomponents.

Biosynthesis of C1r and C1s subcomponents has been studied using monocytes and macrophages, hepatocytes and hepatoma cell lines or fibroblasts. Both proteins have been detected in supernatants and cell lysates as proenzymic monocatenar molecules. C1r and C1s were secreted by stimulated monocytes and by Hep G2 cells, according to a 1:1 stoichiometry. Monocyte C1s secretion was enhanced by lymphokines, such as alpha- or gamma-interferon or by placental soluble factors. Expression of both proteins was coordinately modulated by a newly purified 14 kDa lymphokine at a pretranslational level. Data from in vitro RNA translation are discussed.

Animals↗
PubMed1994

Functional analysis of the serpin domain of C1 inhibitor.

To analyze the role of the heavily glycosylated amino-terminal domain of C1 inhibitor in protease inhibitory activity, two truncated C1 inhibitor molecules were constructed. The abilities of the recombinant truncated inhibitors to complex with target proteases were compared with that of the wild-type recombinant protein. One recombinant truncated molecule consisted of amino acid residues 76 to 478 (C-serp(76)) and the other of residues 98 to 478 (C-serp(98)). The recombinant proteins were each expressed in similar quantities. The thermal denaturation profiles of the two truncated proteins were similar to that of the wild-type protein. Identical binding of C1s, C1r, kallikrein, and beta factor XIIa was observed with the three molecules. Furthermore, the truncated molecules also effectively inhibited C1 activity in hemolytic assays. These studies therefore clearly demonstrate that the amino-terminal domain of C1 inhibitor does not influence complex formation with target proteases.

Complement C1 Inactivator Proteins↗
PubMed1988

A monoclonal antibody to C1q which appears to interact with C1r2C1s2-binding site.

A monoclonal antibody (SB-4) to human C1q was prepared. The equilibrium constant of the antibody for C1q was found to be greater than 10(10) M-1. It has been shown that the antibody binds to the A-B chain dimer, probably via the B chain of C1q. Pepsin digestion of C1q at pH 4.5, which fragments the globular regions but leaves the collagenous region intact, allowed the demonstration that the antigenic site is located in the collagenous region of the molecule. The effect of the antibody on haemolytic activity has shown that it is capable of inhibiting the formation of EAC1 cells from EAC1q cells plus C1r and C1s but is incapable of inhibiting the C1 activity of performed EAC1 cells. This indicates that the binding of the antibody to the collagenous portion of the B chain of C1q probably prevents interaction between C1q and the C1r2-C1s2 complex.

Antibodies, Monoclonal↗
PubMed1982

Dissociation of C1 and concentration dependence of its activation kinetics.

The activation of the zymogen C1s to the enzyme C1s in the human C1 complex [C1q(c1rC1s)2] was studied as a function of the concentrations of (C1rC1s)2 and C1q which were saturated with oligomers of rabbit IgG. A large concentration dependence of the sigmoidal kinetics was observed in the 2-180 nM concentration range. This was explained by association-dissociation equilibria between the antibody-saturated C1q and various forms of the (C1rC1s)2 complex (unactivated to activated). The establishment of these equilibria (binding constant 2 x 10(7) M-1) was assumed to be fast as compared to the rates of the activation steps (rate constants 10(-3) and 10(-2) sec-1 at 30 degrees C). The fast re-equilibration of the C1 complex explains the finding that small amounts of antibody-saturated C1q catalysed the activation of large amounts of C1s. The interpretation of the kinetic results was supported by a direct demonstration of the dissociation of C1 into C1q and (C1rC1s)2 by analytical and density gradient centrifugation. No difference was found between the rates of activation and the dissociation properties of reconstituted C1 and C1 isolated from serum.

Centrifugation, Density Gradient↗
PubMed1999

[Activation of plasma cascade systems in sepsis: role of C1 inhibitors].

During sepsis the complement system, the contact activation system and the coagulation cascade are activated. Activation of these plasmatic cascades contributes to the development of multiple organ failure and the high mortality rate of severe sepsis and septic shock. C1-inhibitor is the main inhibitor of the classical pathway of the complement system (C1s and C1r), of the contact activation system (factor XIIa and kallikrein) and of the intrinsic pathway of coagulation (factor XIa). During sepsis, C1-inhibitor is proteolytically inactivated. The increase of inactivated C1-inhibitor in plasma correlates positively with mortality in septic patients. C1-inhibitor substitution has been shown to reduce the mortality in experimental animals with severe sepsis or septic shock. Only a few cases of C1-inhibitor substitution in patients with severe sepsis or septic shock have been reported. C1-inhibitor has been shown to attenuate the activation of the complement system and the contact activation system and to improve hypotension. Based on this convincing pathophysiological concept and the results of the animal studies, we initiated the "Bernese C1-inhibitor study", a randomised double-blind and placebo-controlled pilot study involving administration of C1-inhibitor to patients with severe sepsis or septic shock. If the results of this pilot study confirm the results of the reports mentioned above, they will serve as a base for larger multicentre studies.

Complement Activation↗