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PubMed1989

Structure and function of C1r and C1s: current concepts.

C1r and C1s, the constituent proteins of C1s-C1r-C1r-C1s, the Ca2+ -dependent catalytic unit of C1, are homologous serine proteinases that share a common activation pattern and have similar structural organizations at the monomeric level. In both cases, activation occurs through cleavage of a single Arg-Ile bond, which converts the single-chain proenzymes into active proteinases comprising two chains linked by a single disulphide bridge. Both NH2-terminal A chains are sub-divided into five structural units (I-V) including a single copy of an Epidermal Growth Factor-like segment (II) and two different pairs of internal repeats (I/III and IV/V). Regions I and III have no equivalent in other proteins, whereas regions IV and V are homologous to short consensus repeats found, in particular, in complement proteins C2, B, H, C4b-binding protein and CR1. The COOH-terminal B chains are homologous to the catalytic chains of serine proteinases, but lack the "histidine-loop", a disulphide bridge common to all other known mammalian serine proteinases. Overall sequence comparison of C1r and C1s reveals 40% amino acid identity and conservation of all cysteine residues. In contrast, C1r and C1s widely differ from each other by their glycosylation patterns: both proteins contain Asn-linked carbohydrates, but four glycosylation sites are present on C1r, and only two on C1s.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

The C1 inhibitor deficiency. A review.

C1 inhibitor (C1I), a member of the serine protease inhibitor superfamily, is the principal regulator of the activation classical pathway of complement by reducing the proteolytic activity of activated C1r and C1s. A deficiency of active C1 inhibitor is the most commonly identified genetic defect of the complement system. It is associated with a pathology called angioedema. There are three forms of hereditary angioedema. The first type is characterized by an insufficient production of a normal protein. The two other forms are characterized by the presence of an abnormal C1 inhibitor protein. Moreover a reduction of functional C1 inhibitor may also be acquired. There are two types of acquired angioedema, a form associated with malignancy (B cell lineage, breast cancer, ...) and an autoimmune form. Angioedema manifests itself by attacks of swelling of the extremities, face, trunk, airways, or abdominal viscera, occurring spontaneously or as a result of trauma. Three main categories of substances have been proposed for the treatment of C1 deficiencies: the androgens, the antifibrinolytics and fresh plasma or purified C1 inhibitor. To distinguish between the different forms of C1 inhibitor deficiencies, it is necessary to determine the amount of C1 inhibitor protein and the level of its functional activity. Several methods for the determination of C1 inhibitor have been proposed: titrimetric and spectrophotometric assays, inhibition of complement haemolytic activity, radioimmunoassay, enzyme-linked immunosorbent assay, ...), in order to improve the diagnosis and the treatment of angioedema.

Angioedema↗
PubMed1994

Identification of defensin binding to C1 complement.

In human serum we found strong defensin binding to the complexes of activated C1 complement (C1) and C1 inhibitor (C1i). Purified C1q, activated C1 tetramer (r2s2) and C1i did not bind defensin. When r2s2 was dissociated by EDTA, only the activated C1s (C1s) bound defensin. Binding of defensins to C1 complement represents a newly recognized bridge between the complement- and phagocyte-mediated host defenses, and a potential mechanism for protecting infected tissue from cytotoxic injury by defensin.

Animals↗
PubMed1989

Terminal complement complexes and C1/C1 inhibitor complexes in autoimmune thyroid disease.

The potential role of complement activation and the membrane attack complex in the pathogenesis of Graves' disease and Hashimoto's thyroiditis has been investigated by measuring serum concentrations of the C1r-C1s-C1 inhibitor complex (C1/C1-inh) and the terminal complement complex (TCC), and by studying the binding to thyroid tissue of monoclonal and polyclonal antibodies against TCC neoantigens. Serum C1/C1-inh and TCC concentrations were significantly increased in 29 patients with untreated Graves' disease compared with 47 healthy subjects (P less than 0.001 for both), and decreased significantly after carbimazole treatment in 18 of these patients for whom post-treatment samples were available (P less than 0.01 and P less than 0.02, respectively). The serum TCC concentration, but not that of C1/C1-inh, was also significantly increased in 15 patients with Hashimoto's thyroiditis compared with the 47 healthy subjects (P less than 0.001). TCCs were identified by immunohistochemical staining around the thyroid follicles in thyroidectomy specimens from patients with Graves' disease (six out of six) and Hashimoto's thyroiditis (two out of two); normal thyroid tissue from two subjects showed no staining. These results suggest a role for complement, in particular the membrane attack complex in the pathogenesis of autoimmune thyroid disease.

Adolescent↗
PubMed1983

Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.

Hereditary angioedema (HAE) is due to a functional deficiency of the inhibitor of the activated first component of complement (C1 INH). This abnormality is thought to be responsible for the generation of a kininlike peptide in HAE plasma that is derived from the second component of complement (C2). Specifically, a combination of C2 cleavage by C1s and C2 fragment cleavage by plasmin has been reported to generate a kinin that is distinguishable from bradykinin. We have attempted to generate this peptide by activating the classical complement pathway by incubation of plasma with immune complexes and then adding plasmin or by incubating purified C1s with C4 and C2 and then adding either plasmin or trypsin. We performed a total of 13 experiments, and in no case was a kininlike molecule generated as assessed by contraction of the estrus rat uterus. However, incubation of EDTA-treated HAE plasma at 37 degrees C for time intervals up to 1 hr progressively generated a smooth muscle-contracting activity. This activity was resistant to tryptic digestion but was destroyed after incubation with carboxypeptidase B, an inhibition profile consistent with that of bradykinin. We therefore propose that bradykinin alone, or in combination with other factors heretofore unrecognized, might be responsible for the swelling that is characteristic of hereditary angioedema.

Angioedema↗
PubMed1994

Activation of human complement serine-proteinase C1r is down-regulated by a Ca(2+)-dependent intramolecular control that is released in the C1 complex through a signal transmitted by C1q.

The activation of human C1, a Ca(2+)-dependent complex proteinase comprising a non-enzymic protein, C1q, and two serine proteinases, C1r and C1s, is based primarily on the intrinsic property of C1r to autoactivate. The aim of the present study was to investigate the mechanisms involved in the regulation of C1r autoactivation, with particular attention to the role of Ca2+ ions. Spontaneous activation of proenzyme C1r was observed upon incubation in the presence of EDTA, whereas Ca2+ ions reduced markedly the activation process. Several lines of evidence indicated that Ca2+ inhibited the intramolecular activation reaction but had little or no effect on the intermolecular activation reaction. C1q caused partial release of this inhibitory effect of Ca2+. Complete stabilization of C1r in its proenzyme form was obtained upon incorporation within the Ca(2+)-dependent C1s-C1r-C1r-C1s tetramer, and a comparable effect was observed when C1s was replaced by its Ca(2+)-binding alpha-fragment. Both tetramers, C1s-C1r-C1r-C1s and C1s alpha-C1r-C1r-C1s alpha, readily associated with C1q to form 16.0 S and 14.7 S complexes respectively in which C1r fully recovered its activation potential. Both complexes showed indistinguishable activation kinetics, indicating that the gamma B catalytic region of C1s plays no role in the mechanism that triggers C1r activation in C1. The collagen-like fragments of C1q retained the ability to bind to C1s-C1r-C1r-C1s, but, in contrast with intact C1q, failed to induce C1r activation in the resulting complex at temperatures above 25 degrees C. On the basis of these observations it is proposed that activation of the serine-proteinase domain of C1r is controlled by a Ca(2+)-dependent intramolecular mechanism involving the Ca(2+)-binding alpha-region, and that this control is released in C1 by a signal originating in C1q and transmitted through the C1q/C1r interface.

Calcium↗
PubMed1975

Complement components in normal serum and plasma quantitated by electroimmunoassay.

Sjöholm, A. G. Complement Components in Normal Serum and Plasma Quantitated by Electroimmunoassay. Scand. J. Immunol. 4, 25-30, 1975. The concentrations of C1q, C1s, C3, C4, C5, C3 proactivator, and C1 inactivator in serum and EDTA plasma from 100 normal adults were determined by electroimmunoassay. The normal range of each of the proteins is given. The C1q values varied more closely with the C1s values than with the levels of the other complement components. C3, C5, and C3 proactivator seemed to form a fairly interdependent group. The reproducibility of double determinations (interplate variation) was 4.9% to 7.9%. The variation of the complement component levels on repeated sampling from normal individuals was investigated. Also, repeated freezeing and thawing and storage at room temperature of serum and plasma were studied for their effect on the quantitation of the complement components. C3 and C4 values obtained by electroimmunoassay were in agreement with the values obtained by single radial immunodiffusion.

Adult↗
PubMed2005

Immune function of C1q and its modulators CD91 and CD93.

C1q is a subcomponent of the first component of complement C1, which is a multimolecular complex comprising one molecule of C1q and two molecules each of the autoreactive proteases, C1r and C1s. This multimolecular complex triggers the classical pathway of complement. Advances in the past several years have provided a partial crystal structure of the C1q subunit. This, together with gene deletion of C1q, has allowed further insight into the multifunctional immune aspects of this molecule. Two C1q-mediated functions that have received intense scrutiny recently are C1q-mediated apoptotic clearance of cell debris and phagocytosis. This has led to a heightened search for specific receptors for the collagen-like region (CLR) as well as the globular heads. Two transmembrane proteins, CD91 and CD93, have been proposed to interact indirectly with the CLR of C1q, promoting apoptotic clearance and phagocytosis, respectively. The aim of this article is to provide an overview of the structural and functional information that implicates CD91 and CD93 in C1q-mediated functional effects.

Animals↗
PubMed1993

Assembly of the C1 complex.

The C1 complex of complement is a Ca(2+)-dependent complex protease comprising two loosely interacting subunits. C1q, the recognition subunit, is an hexameric protein with six peripheral globular domains, each connected through collagen-like "arms" to a central fibril-like "stalk". The catalytic subunit, C1s-C1r-C1r-C1s, is a Ca(2+)-dependent tetrameric association of two serine protease zymogens, C1r and C1s, that are sequentially activated by cleavage of a single peptide bond, upon binding of C1 to activators. Each monomeric protease is comprised of six structural motifs which form at least four domains, distributed in two functionally distinct regions, alpha (N-terminal) and gamma-B (C-terminal). The catalytic (gamma-B) regions of C1r and C1s are respectively located in the centre and at each end of the isolated tetramer, and the Ca(2+)-dependent C1r-C1s associations are mediated by the interaction (alpha) regions, which contain one Ca2+ binding site each. Physicochemical and electron microscopy studies indicate that the tetramer, which is highly elongated, folds into a more compact conformation upon interaction with C1q. Various models for C1 have been proposed, in which the tetramer either interacts with the outside part of the C1q arms (O- and W-shaped models), or is folded within the C1q arms (S- or 8-shaped models). These models are discussed in light of available information and in consideration of the structural requirements of C1 activation and function.

Complement C1↗
PubMed1989

Acceleration of site-to-site transfer of C1- by a monoclonal antibody to C1-s.

A monoclonal antibody to human C1-s (a subcomponent of C1-), M365 blocked the complement-mediated lysis of C1(-)-coupled IgM-sensitized sheep erythrocytes (EAIgMC1). However, M365, via its binding to C1-s, did not inhibit C2 activation and only partially inhibited C4 activation, both attributable to the proteolytic action of C1s. Therefore, the inhibition of lysis of EAIgMC1 is not due to the direct effect of antibody binding to C1-s in the C1- molecule. M365, when added to the pre-formed EAIgMC1, deprived the whole C1 molecule from the cells. It was also found that M365-bound C1 could not bind to EAIgM. These phenomena were induced only when M365, one of seven monoclonal antibodies to C1-s, was employed and when IgM antibody-sensitized E was used. The observed C1- liberation and C1 binding inhibition by M365 were found to be less effective when the C4b bearing cells, EAIgMC4, were used. But the addition of M365-bound C1- to EAIgMC4 promoted the formation of the C3 convertase, C4b2a, which caused an incremental lysis of the C4b bearing cells. The results are interpreted to mean that C1-, once complexed with M365, still remains active and acquires the ability to transfer from one C1 binding site on IgM to another to activate the convertases. C4b must be a prerequisite on the cells to induce the effective C1- transfer and resulting increase of C3 convertase sites. We hypothesize that the M365-C1-s association alters the conformation of C1q and thereby leads to the dissociation of whole C1- from IgM. The M365-C1- complex, therefore, can move from site to another.

Animals↗
PubMed2000

Serine proteases of the complement system.

The complement system in blood plasma is a major mediator of innate immune defence. The function of complement is to recognize, then opsonize or lyse, particulate materials, including bacteria, yeasts and other microrganisms, host cell debris and altered host cells. Recognition occurs by binding of complement proteins to charge or saccharide arrays. After recognition, a series of serine proteases is activated, culminating in the assembly of complex unstable proteases called C3/C5 convertases. These activate the complement protein C3, which acts as an opsonin. The complement serine proteases include the closely related C1r, C1s, MASPs 1-3 (80-90 kDa), C2 and Factor B (100 kDa), Factor D (25 kDa) and Factor I (85 kDa). Each of these has unusually restricted specificity and low enzymic activity. The C1r, C1s and MASP group occur as proenzymes. When activated, they are regulated, like many plasma serine proteases, by a serpin, C1-inhibitor. C2 and Factor B, however, have complex multiple regulation by a group of complement proteins called the Regulation of Complement Activation (or RCA) proteins, whereas Factors I and D appear to have no natural inhibitors. Advances in structure determination and protein-protein interaction properties are leading to a more detailed understanding of the complement-system proteases, and are indicating possible new routes for potential therapeutic control of complement.

Animals↗
PubMed1987

Calcium-sensitive thermal transitions and domain structure of human complement subcomponent C1r.

Fluorescent probes and other methods have been used to investigate the thermal stability of activated C1r and functionally intact fragments isolated from tryptic digests of the protein. This enzyme exhibits two irreversible transitions that differ with respect to their sensitivity to metal ions. The high-temperature transition occurs with a midpoint near 53 degrees C in 0.02 M tris(hydroxymethyl)aminomethane buffer and 0.15 M NaCl, pH 7.4. It is relatively insensitive to Ca2+ and ionic strength and is accompanied by a loss of catalytic activity. The low-temperature transition is most easily observed in the presence of ethylenediaminetetraacetic acid and is completely abolished by 100 microM Ca2+. Its midpoint varies between 26 degrees C at low ionic strength and 40 degrees C in the presence of 0.5 M NaCl. The low-temperature transition results in extensive polymerization of the protein without loss of the esterolytic activity or the ability to react with C1 inhibitor; however, the ability to reconstitute hemolytically active C1 or even bind to C1s in the presence of Ca2+ is destroyed. A highly purified N-terminal fragment generated by tryptic digestion of C1r in the presence of Ca2+ retained its ability to interact with C1s, disrupting the formation of C1s dimers in the presence of Ca2+. In the absence of Ca2+, this fragment displays only a low-temperature transition that is very similar to the one observed with the whole protein and that destroys its ability to bind to C1s. Addition of Ca2+ stabilizes this fragment, shifting the midpoint of its melting transition upward by more than 20 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilino Naphthalenesulfonates↗
PubMed1994

The structure and function of the first component of complement: genetic engineering approach (a review).

The availability of cDNA and genomic clones for the subcomponents of C1, as well as the recognition of the modular organization of serine-proteases have opened up exciting new possibilities for approaching structural problems. In this review the latest achievements of combined protein engineering, functional and structural studies are summarized. The concept of this research is to construct deletion, point and hybrid mutants of the highly homologous C1r and C1s subcomponents, to reveal the functional role of individual modules, map the interaction sites between subcomponents of the C1 complex and refine the structural model of C1. The first prerequisite of such an approach was the expression of the subcomponents in a eukaryotic system, in biologically active form. This was followed by expression of various mutants. Autographa californica nuclear polyhedrosis virus was used as vector to express human C1r and C1s in Spodoptera frugiperda cell culture and in lepidopteran larvae. The yield of expression was high enough to isolate recombinant subcomponents for structural and functional studies. Recombinant viruses containing the A-, B-, and C-chains of C1q were also constructed. The insect cells are able to beta-hydroxylate the Asn residue of the EGF domain in the C1r but with a low efficiency. It is clear now, that this post-translational modification does not play a role in the Ca2+ dependent C1r-C1s interaction. The results with deletion mutants of C1r show that both, domain I, and II are absolutely necessary for the tetramer formation and both have regulatory role in the autoactivation. The C1s alpha R hybrid does not dimerize in presence of Ca2+, however it can form a tetramer with C11(2) that can bind to C1q. This observation indicates that the function of the C1s alpha part in the hybrid is modulated by the C1r part (gamma B) of the molecule. The C1Rs hybrid behaves like C1r, providing haemolytically active C1 with C1q and C1s. This observations shows that the regulatory domains determine the high functional specificity of the serine-protease subcomponents of C1. In order to control the autoactivation process point mutant cDNAs were constructed by altering the Arg-Ile bond in the catalytic domain of the C1r. The Gln-Ile construction is a stable zymogen while the Arg-Phe mutant has a lower rate of autoactivation.

Animals↗
PubMed1992

[Complement system in status asthmatics--analysis of anti-complementary effects induced by methylprendisolone].

Complement system was investigated in 7 patients with status asthmatics treated with large doses of methylprednisolone (MPS). Complement hemolytic activities, complement protein profile, complement fragments and circulating immune complexes were measured before, 3 and 8 hours after and 14 days after MPS administration. MPS normalized C4 and C1INH activities 6 hours after administration. MPS also decreased ACH50 6 hours after administration and D activity 3 and 6 hours after, but these activities recovered to their previous normal range within 14 days. P and H were decreased at each measurement time, and C1s was transiently decreased 6 hours after MPS administration. Complement fragment iC3b was increased at each measurement time, but fragment Bb tended to be decreased 14 days after MPS administration. The increment of anaphylatoxin C3a recovered to normal 14 days after MPS administration. In vitro experiments, MPS inhibited D and C1s activation directly, and decreased the decay of B and C4. Inhibition of C1s might also increase C1INH activity clinically. These results clarified that the alternative complement pathway was activated, and suggested that the C1 bypass pathway might be also activated in status asthmatics. It was further considered that these anti-complementary effects induced by MPS, brought about an improvement in asthmatic symptoms. Studies to identify the complement activators continued, and circulating immune complexes may possibly be one of those agents activating complement cascade.

Adult↗
PubMed1975

Studies on human plasma C1 inactivator-enzyme interactions. I. Mechanisms of interaction with C1s, plasmin, and trypsin.

This study has explored the nature of the molecular events which occur when C1 inactivator, a human plasma inhibitor of the complement, kinin-forming, coagulation, and fibrinolytic enzyme systems, interacts with C1s, plasmin, and trypsin. Purified inhibitor preparations demonstrated two bands, when examined by acrylamide gel electrophoresis in the presence of sodium dodecyl sulfate (SDS). The molecular weights of the major and minor bands were 105,000 and 96,000 daltons, respectively. The minor component appeared to be immunologically and functionally identical to the main C1 inactivator component. Loss of C1s and plasmin functional activity was associated with the formation of a 1:1 molar complex between the inhibitor and each enzyme. These complexes were stable in the presence of SDS and urea. The light chain of both these enzymes provided the binding site for C1 inactivator. Complex formation and enzyme inhibition occurred only with native and not with an inhibitor preparation denatured by acid treatment, thereby demonstrating the importance of conformational factors in the enzyme-inhibitor reaction. Although peptide bond cleavage of the C1 inactivator molecule by C1s was not documented, plasmin was found to degrade the inhibitor with the production of several characteristic derivatives. At least one of these products retained the ability to complex with C1s and plasmin. Trypsin, which failed to form a complex with C1 inactivator, degraded the inhibitor in a limited and sequential manner with the production of nonfunctional derivatives one of which appeared structurally similar to a plasmin-induced product. These studies therefore, provide new information concerning the molecular interactions between C1 inactivator and several of the proteases which it inhibits.

Animals↗
PubMed2000

Distinct pathways of mannan-binding lectin (MBL)- and C1-complex autoactivation revealed by reconstitution of MBL with recombinant MBL-associated serine protease-2.

Mannan-binding lectin (MBL) plays a pivotal role in innate immunity by activating complement after binding carbohydrate moieties on pathogenic bacteria and viruses. Structural similarities shared by MBL and C1 complexes and by the MBL- and C1q-associated serine proteases, MBL-associated serine protease (MASP)-1 and MASP-2, and C1r and C1s, respectively, have led to the expectation that the pathways of complement activation by MBL and C1 complexes are likely to be very similar. We have expressed rMASP-2 and show that, whereas C1 complex autoactivation proceeds via a two-step mechanism requiring proteolytic activation of both C1r and C1s, reconstitution with MASP-2 alone is sufficient for complement activation by MBL. The results suggest that the catalytic activities of MASP-2 split between the two proteases of the C1 complex during the course of vertebrate complement evolution.

Carrier Proteins↗
PubMed1979

The isolation and characterization of bovine C4a, an activation fragment of the fourth component of complement.

The fourth component of bovine complement, C4, was cleaved specifically by subcomponent C1s to produce two fragments, C4a and C4b. The smaller, C4a, was isolated in pure form and is a peptide of 9500 mol.wt. containing approx. 84 amino acids and no detectable carbohydrate. C4a has an amino acid composition that is comparable with the anaphylatoxins C3a and C5a, containing six cysteine residues/mol and a high proportion of basic residues. The amino acid sequence of the first thirteen residues shows four identities with the porcine C3a sequence. There is almost complete identity between the C4a sequence and that of the alpha-chain of human C4, indicating that this region is highly conserved. This evidence also clearly establishes that C4a is cleaved from the N-terminal of the alpha-chain of C4.

Amino Acid Sequence↗
PubMed1990

Chemical and functional characterization of a fragment of C1-s containing the epidermal growth factor homology region.

C1-s, one of the three subcomponents of C1-, the first component of complement, is a serine protease comprising two disulfide-linked chains, the B chain, containing the catalytic site, and the A chain, involved in Ca2+ binding and Ca2(+)-dependent interaction(s) with the other C1- subcomponents. In an attempt to identify the regions responsible for the latter functions, C1-s was submitted to limited proteolysis with plasmin, a treatment that split the A chain into three major fragments, alpha 1, alpha 2, and gamma. Fragment alpha 2, which comprised the epidermal growth factor-like (EGF-like) region of C1-s, was heterogeneous, starting at serine 97 or phenylalanine 105 and ending at lysine 195. This fragment was reduced and alkylated and then digested with elastase, and three peptides covering positions 131-135, 131-139, and 131-140 were characterized by amino acid analysis, Edman degradation, and mass spectrometry, showing that position 134 of C1-s is occupied partly by an asparagine (47%) and partly by an erythro-beta-hydroxyasparagine, in contrast with the homologous position (150) of C1-r which only contains erythro-beta-hydroxyasparagine. As measured by equilibrium dialysis, native alpha 2, like the other plasmin-cleavage fragments, did not retain the ability of intact C1-s to bind Ca2+. In the same way, plasmin cleavage abolished the ability of C1-s to dimerize or to associate with C1-r in the presence of Ca2+. In contrast, both alpha 2 and the N-terminal alpha 1 fragment, starting at serine 24 of the A chain, were able to compete significantly with intact C1s for the formation of the Ca2(+)-dependent C1-s-C1r-C1-r-C1-s tetramer.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗