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PubMed1990

Neutron scattering study of the (gamma-B) catalytic domains of complement proteases activated C1r and C1s.

The catalytic domains of activated C1r and C1s, comprising the C-terminal region of the A chain (gamma), disulphide-linked to the B chain, were obtained by limited proteolysis of the native proteases with chymotrypsin and plasmin, respectively, and studied by small angle neutron scattering. For activated C1s (gamma-B), a molar mass of 45,000 +/- 5000 g/mol, and a relatively large radius of gyration (Rg) of 28 +/- 1 A were determined, excluding a single globular domain. The corresponding values for activated C1r (gamma-B)2 (90,000 g/mol, Rg = 34 +/- 1 A) are consistent with a dimer involving the loose packing of two (gamma-B) subunits. Various models of the dimer are discussed in the light of neutron scattering and other data.

Chymotrypsin↗
PubMed1987

Quantitation of (C1INH)2 C1r-C1s complexes in glomerulonephritis as an indicator of C1 activation.

C1 activation was assessed in several forms of glomerulonephritis by radioimmunoassay quantitation of circulating (C1INH)2 C1r-C1s complexes (INC). Eight patients with active systemic lupus erythematosus (SLE) and nephritis had elevated serum INC (mean = 15.3 vs control = 5.8, P less than 0.01). Their INC levels were normal during remission. Serum INC had a weak inverse correlation with serum C1q greater than 3 mg/dl (r = 0.42, P = 0.02). In longitudinal studies, serum INC also had a weak inverse correlation with serum C3 and C4. Only 1 of 10 patients with type I and 1 of 15 with type III membrano-proliferative glomerulonephritis (MPGN) had elevated serum INC. No patient with type II MPGN had elevated levels. Two of 10 patients with poststreptococcal glomerulonephritis (P-SGN) had elevated serum INC, but all normalized with convalescence. Patients with IgA nephropathy had normal serum INC. The data demonstrate the importance of C1 activation in SLE and P-SGN. The mechanism of complement activation in types I and III MPGN remains unclear; the data suggest, but do not prove, that C1-independent complement activation may occur in these patients.

Antigen-Antibody Complex↗
PubMed1989

Models for C1. Tools or toys? The real biological challenge.

C1 modelling, based on structural and functional data, does not yet bring the different laboratories to a consensus on C1 activation, activity and associated controls. The heart of C1 beats in its subcomponent C1r2, which, from its domain structure and its twinning with subcomponent C1s, represents the challenge for the knowledge of C1. The 8-shaped model proposed for the C1r2-C1s2 association, with a head-to-tail interaction between the C1r catalytic domains, appears as the hub of an active world in the bosom of C1q. More detail is now required on protein-protein interactions inside C1 to refine the available models or to propose alternatives. Precise data on the interactions of C1 proteins with activators, substrates or control proteins are also likely to bring pertinent help in proposing future models for C1.

Binding Sites↗
PubMed1987

Isolation and analysis of immune complexes from sera of patients with polymyalgia rheumatica and giant cell arteritis.

Serum samples were obtained from patients with polymyalgia rheumatica (PMR: n = 10) or giant cell arteritis (GCA; n = 7), or both. Samples were taken either before treatment or within one week of starting prednisolone. Immune complexes (IC) were concentrated by polyethylene glycol (PEG) precipitation then purified with either IgG anti-C1q-Sepharose or IgG anti-C3c-Sepharose. Complex components were separated by sodium dodecyl sulphate (SDS) gradient polyacrylamide gel electrophoresis then transferred to nitrocellulose by Western blotting. Identification of proteins was carried out using specific antisera. All the IC contained IgM (mu chain), some contained IgA (alpha chain), and IgG (gamma chain). C1r, C1s, C1q, C3, C4, and C reactive protein (CRP), where tested, were found in most but not all IC. The occurrence of properdin, factor B, alpha 2 macroglobulin (alpha 2M), factor H (beta 1H), C1 esterase inhibitor, and C4 binding protein was also investigated. Immune complexes in PMR and GCA differed from those previously characterized in rheumatoid arthritis (RA)1 purified by anti-C1q-Sepharose which contained immunoglobulins and C1q only. No properdin or factor B were detected in RA IC purified with either anti-C1q-Sepharose or anti-C3c-Sepharose.

Aged↗
PubMed1985

Primary structure of the reactive site of human C1-inhibitor.

Human C1-inhibitor (C1-Inh) forms an equimolar complex with complement proteinase C1s that is resistant to dissociation by sodium dodecyl sulfate. The formation of this stable complex results in the cleavage of a peptide bond near the carboxyl terminus of the inhibitor and, whereas the bulk of C1-Inh remains covalently bound to the light chain of C1s, the postcomplex inhibitor peptide can be isolated under denaturing conditions. We have sequenced the amino-terminal region of this peptide and deduced that it represents the carboxyl-terminal side of the reactive site of C1-Inh. Limited proteolysis of C1-Inh by Crotalus atrox protease results in an active derivative lacking an amino-terminal peptide of 36 residues. Further proteolysis of this derivative with Pseudomonas aeruginosa elastase inactivates the inhibitor and a peptide is released. The amino-terminal sequence of this peptide overlaps with that of the postcomplex peptide and indicates that the residue imparting primary specificity to the inhibitor is arginine.

Amino Acid Sequence↗
PubMed1992

Dynamic equilibria between subcomponents of C1, the first component of human complement.

C1r and C1s, the serine protease components of activated C1, form a tetramer in the presence of Ca2+. The stability of this tetramer is sufficient that its association with the third component, C1q, has been successfully treated as a reversible bimolecular equilibrium reaction [Siegel and Schumaker, Molec. Immun. 20, 53-66 (1983)]. We have used the fluorescence anisotropy (A) of fluorescein-labeled C1s (s*) to monitor assembly and subcomponent exchange in 0.15 mol/l NaCl, 0.001 mol/l Ca2+ 0.02 mol/l Tris, pH 7.4. Addition of q to r2s*2 causes a small but measurable delta A of 0.01-0.02. The response is too fast to measure at 37 degrees but can be readily followed at 4 degrees where t 1/2 = 0.6 min when [q] = [r2s*2] = 0.5 mumol/l. The increase in A can be readily reversed by dilution or by addition of unlabeled C1s. Slow incremental addition of q to a solution of r2s*2 produces a dose-dependent delta A from which stoichiometry and dissociation constants can be derived. Measurements of Kd as a function of temperature establish an inverse temperature dependence with delta H = -15 kcal/mol and a value of Kd = 0.031 mumol/l at 37 degrees (delta G = + 11, T delta S = -26 kcal/mol). Thus, the assembly process appears to be entropy-driven presumably due to the exclusion of structured water from protein-protein interfaces in the complex.

Complement C1r↗
PubMed1976

Isolation of two forms of activated C1s, a subcomponent of the first component of rabbit complement.

Two forms of activated C1s, a subcomponent of the first component of complement, were present in preparations of C1 specifically purified from rabbit serum by affinity chromatography on IgG-Sepharose 6B and were separated by DEAE-cellulose chromatography in the presence of EDTA. These two activated C1s, designated C1s(I) and C1s(II), were indistinguishable with regard to hemolytic activity as well as C1s esterase activity, though they had different molecular weights. C1s(I) had a molecular weight of 106,000, consisting of H and L chains connected by disulfide bonds; the molecular weights of the chains were 70,000 and 36,000, respectively. On the other hand, C1s(II), with a molecular weight of 72,000, consisted of two chains each with a molecular weight of about 37,000, which were also connected by disulfide bonds. These results suggest that, in the case of rabbit C1s, the primary product of activation with C1r, C1s(I), may be susceptible to further cleavage of its H chain without any loss of C1s activity, resulting in the formation of C1s(II), though the active principle responsible for this conversion remains to be elucidated.

Animals↗
PubMed1981

Influence of age and sex on serum complement components in children.

Concentrations of eight complement components were determined on sera from 419 healthy children (198 boys and 221 girls) aged from 1 to 19 years. A significant correlation between concentration and age for all complement components (C1q, C1s, C4, C3, C5, factor B, properdin, and C1 inhibitor) was observed for girls; in the male population, a significant correlation was present only for C1q, C4, C3, C5, and properdin. The presence of a significant relationship to age suggests that this variable must be considered in establishing normal values of serum complement for children.

Adolescent↗
PubMed1985

C56 formation in the reaction mixture of isolated complement components through the classical complement pathway.

The mechanism of hemolysis of unsensitized erythrocytes by a mixture of 9 isolated, human-derived complement components, C1s, C4, C2, C3, C5, C6, C7, C8 and C9 (C1s-C9) was studied. Of the tested erythrocytes, guinea pig erythrocytes (Egp) were the most susceptible to lysis by C1s-C9, followed by human and sheep erythrocytes. Contamination of the isolated complement components by C56 was ruled out. It was determined that a factor was generated in the reaction mixture of C1s, C4, C2, C3, C5 and C6 (C1s-C6), which had lytic activity against Egp when C7, C8 and C9 were added. We found that the lytic factor was similar to C56 in the following properties: (1) the activity of the lytic factor decreased when incubated with isolated C7 prior to its reaction with Egp; (2) the lytic factor did not bind to Egp by itself but it did bind in the presence of C7; (3) EDTA did not have any inhibitory effect on the lytic factor; (4) the activity of the lytic factor decreased by treatment with anti-C5 and anti-C6 but not by treatment with anti-C3 and anti-C4, and (5) gel filtration of the reaction mixture (C1s-C6) indicated that the elution volumes of the lytic factor and of isolated C56 were similar. Thus, it is likely that C56 is generated in the reaction mixture of C1s-C6 and the lytic factor binds to unsensitized erythrocytes together with C7, to form an intermediate EC567 which is susceptible to lysis by the action of C8 and C9.

Animals↗
PubMedDate not supplied

Complement aberrations in serum from children with otitis due to S. pneumoniae or H. influenzae.

Complement components C1q, C1s, C3, C4, factor B and properdin were measured, together with C1 subcomponent complexes and Cq binding substances in acute and convalescent samples from patients with relapsing and non-relapsing otitis media due to S. pneumoniae and H. influenzae. Analysis of C1 subcomponent complexes together with the finding of low C1q levels gave evidence of a disturbed C1 function in acute OME. Furthermore, complement activation by the classical and by the alternative pathways was demonstrated. Complement aberrations were more pronounced in relapsing otitis than in non-relapsing otitis. C1q binding substances that might possibly cause the complement aberrations found were present in most of the patients.

Acute Disease↗
PubMed1993

Identity of the putative serine-proteinase fold in proteins of the complement system with nine relevant crystal structures.

The serine-proteinase domain is responsible for the proteolytic events that occur during complement activation. The sequences of nine serine proteinases of known crystal structure were compared with the serine-proteinase sequences in the six complement proteins C1r, C1s, C2, factor B, factor I and factor D to assess the degree of structural homology of the latter with the crystal structures. All sequence insertions and deletions were readily located at the protein surface. The internal location of disulphide bridges and the surface location of putative glycosylation sites are compatible with this structure. Secondary-structure predictions for the sequences were fully consistent with the crystal structures. It is concluded that the double subdomain beta-sheet motif is retained in the complement sequences, but that localized differences are observed for factor I, C2 and factor B.

Amino Acid Sequence↗
PubMed1995

Synthesis of complement proteins in amnion.

The amnion is a metabolically active tissue that has been identified as a site of synthesis of numerous products. We report that amnion tissue explants and amnion-derived epithelial cells synthesize and secrete six proteins of the complement system, C1r, C1s, C1 inhibitor, factor B, C3, and factor H. Synthesis of C2 was minimal and variable, and C5 was not detected. The six synthesized proteins had size and subunit composition characteristic of proteins synthesized in HEp2, a long term cell line derived from malignant epithelial cells. Constitutive and regulated synthesis of five of the six proteins was similar in amnion tissue and cells. However, synthesis of factor B was different in tissue and cells; constitutive synthesis was 12-fold higher in tissue than in cells, and interleukin-1 did not alter synthesis in tissue, but increased synthesis by 11.7-fold in cells. These results indicate that amnion may be a source of complement proteins present in the amnion fluid and may contribute to local host defense along with endometrial glandular epithelial cells, which synthesize C3. Furthermore, our results suggest that amnion tissue is stimulated in vivo to synthesize factor B and cannot respond to interleukin-1 with a further increase in the synthesis rate.

Adult↗
PubMed1983

Activation of C1 by soluble IgG aggregates as detected by a novel one-step hemolytic assay that specifically measures the proenzyme form of C1s.

A new hemolytic assay is described that specifically measures the precursor form of the C1s subcomponent of the complement system. The assay employs a C1s-depleted reagent obtained by immunoadsorption of fresh human plasma on immobilized goat anti-human C1s antibodies. Linear Z plots are obtained with nanogram levels of precursor C1s, whereas C1s completely fails to induce hemolysis in the assay. Because low concentrations of C1s do not interfere with the activity of precursor C1s, the assay can be used for the stoichiometric measurement of C1 activation. The precursor C1s assay was applied to the study of C1 binding and activation by soluble aggregates of human IgG (AIgG). Incubation of purified human C1 with AIgG caused a temperature-independent consumption of whole C1 hemolytic activity, indicating binding of C1, but almost no consumption of the total (precursor + activated) C1s activity. On the other hand, activation of C1, measured as the time- and temperature-dependent consumption of precursor C1s, could greatly exceed the binding of C1. These findings can be explained by using recent findings concerning the association-dissociation equilibrium between C1q and the tetrameric complex of C1r and C1s.

Animals↗
PubMed1981

Amino acid sequence around the thiol and reactive acyl groups of human complement component C4.

Activation of the fourth component of complement (C4) by C1s results in the generation of a reactive acyl group, able to react with putrescine, and in the release of a free thiol group that cannot be detected in the native haemolytically active molecule. Both the reactive acyl group and the free thiol group have been shown to reside in C4d, a fragment of the alpha'-chain of C4b derived from digestion of the molecule with the control proteins C3b inactivator and C4-binding protein. Peptides derived from CNBr digestion of [1,4-14C]putrescine-labelled and iodo(2-14C]acetic acid-labelled C4d have been obtained and used to establish a continuous sequence of 88 residues from the N-terminus of the molecule. The thiol and reactive acyl groups are contained in an octapeptide that shows near identity with the equivalent sequences reported for alpha 2-macroglobulin and C3. Other adjacent short sections also show homology of sequence between the three proteins, and it is highly likely that they contribute to the overall structure that gives a unique reactivity to the thiol ester bond postulated to exist in the native forms of the three proteins.

Amino Acid Sequence↗
PubMed1985

Determination of C1s-C1 inhibitor complexes in plasma by means of an enzyme linked immunosorbent assay.

An enzyme linked differential antibody immunosorbent assay for the quantitation of the C1s-C1 inhibitor complex has been developed. A study of the assays' performance under various conditions has shown that before use in the assay, it is imperative to remove competing forms of C1s from the samples to be tested. This is conveniently achieved in human plasma or serum by polyethylene glycol precipitation of the C1qrs, since the C1s-C1 inhibitor complex remains soluble and can be assayed in the supernatant solution. The detection limit of the assay in the plasma milieu is 0.1 mg/l, and the concentrations of the C1s-C1 inhibitor complex were found to be 1 mg/l in citrated plasma and 2 mg/l in serum. Activation of the fibrinolytic system in vivo does not seem to result in any appreciable C1 activation, since there was no concomitant major change in the plasma concentration of the C1s-C1 inhibitor complex.

Adult↗