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PubMed1991

Isolation of human complement subcomponents C1r and C1s in their unactivated, proenzyme forms.

We have modified a standard isolation procedure for C1r and C1s, which employs IgG-Sepharose affinity chromatography followed by DEAE chromatography. As usual, all steps were performed at low temperature and two proteolytic inhibitors, PMSF and NPGB, were added during affinity chromatography on IgG-Sepharose. The novel condition was to keep the pH at pH 6.1 during the entire procedure, where activation was markedly depressed. In addition, purification was improved by washing the IgG-Sepharose column with a buffer free of added divalent cations immediately prior to elution of the C1r and C1s with EDTA. The final yields of highly purified C1r and C1s were about 20%; little or no activated material was detected in these highly purified fractions.

Chromatography, Affinity↗
PubMed1994

Non-coordinated biosynthesis of early complement components in a deficiency of complement proteins C1r and C1s.

We report on a 60-year-old woman with systemic lupus erythematosus and a total (95%) C1r and a partial (36%) C1s deficiency. The patient complained about cutaneous lesions on forearms and legs without other systemic involvement. Elevated anti-nuclear, anti-native DNA and anti-SSA antibodies were present. The finding of persistently depressed levels of haemolytic complement activity (CH50) on both serum and plasma, associated with normal levels of C3, C4 and C2 components, and normal alternative pathway haemolytic activity showed a deficiency of an early component of the classical pathway. Indeed C1r component was below the limits of detection whereas C1s component was lowered (36%). The depressed CH50 was only corrected by purified C1r. Biosynthesis of C1r and C1s by patient's monocytes was spontaneously normal but not up-regulated by interferon-gamma for C1r alone, whereas the biosynthesis of C1s, but also of interleukin-6, was increased, indicating a specific disregulation of C1r. The deficiency was associated with a lupus syndrome and a fatal assumed septic shock. This is in agreement with other reported cases.

Cells, Cultured↗
PubMed1985

Domain structure and associated functions of subcomponents C1r and C1s of the first component of human complement.

The serine protease subcomponents of the activated form of the first component of human complement (C1), C1r and C1s, were observed by electron microscopy after the native proteins and their limited proteolysis products, obtained from autolytic cleavage (C1r) or from incubation with plasmin (C1s) were rotary shadowed. At the monomeric level, both C1r and C1s comprised two globular domains, a smaller interaction domain (corresponding to the NH2-terminal half of the A chain, alpha, and responsible for calcium binding and C1r-C1s interaction) and a larger catalytic domain (corresponding to the COOH-terminal part of the A chain, gamma, disulfide-linked to the B chain and bearing the serine protease active site). The two globular domains are linked by a connecting strand, beta. The (C1r)2 dimer appeared as a "croissant"-like association, where the two monomers interact through their catalytic domains. On the basis of the domain structure of C1r and C1s, a model of the calcium-dependent C1s dimer is proposed, in which the two monomers interact through their NH2-terminal interaction domains; in the same way, a model of the C1s-(C1r)2-C1s catalytic subunit of C1 is presented, in which (C1r)2 forms a core, its distal interaction domains interacting with the corresponding domains of C1s.

Complement Activating Enzymes↗
PubMedDate not supplied

Alternative complement pathway in hypocomplementemic/normal C1s-C1 inhibitor complex patients with SLE.

To test whether alternative complement pathway activation explains normal C1s-C1 inhibitor complex in hypocomplementemic (low CH50cl) patients with systemic lupus erythematosus, we examined alternative pathway hemolytic complement (CH50alt) factor B, and Ba fragment in hypocomplementemic sera with normal and with elevated C1s-C1 inhibitor complex. Sera with and without high C1s-C1 inhibitor complex were similar in CH50cl, C3, and C4. There was little evidence for important alternative complement pathway activation in either group, but patients with classical pathway activation (elevated C1s-C1 inhibitor complex) had slightly lower CH50alt and slightly higher factor B and Ba compared to patients with normal C1s-C1 inhibitor complex. Pregnant patients did not differ from non-pregnant patients. Alternative complement pathway activation does not account for hypocomplementemia in this group of patients.

Complement Activation↗
PubMedDate not supplied

Genetic studies of low-abundance human plasma proteins. VII. Heterogeneity of the C1S subcomponent of the first complement component.

Charge-based structural variation has been observed in the C1s subcomponent of the first complement component C1 after isoelectric focusing and immunoblotting. One common and two uncommon autosomal co-dominantly expressed alleles, designated C1S*1, C1S*2 and C1S*3, have been recognized at the C1S structural locus. The frequency of these alleles was 0.979, 0.016 and 0.005, respectively, in a U.S. white population. No variation at the C1S locus was observed in a U.S. black sample (n = 95).

Alleles↗
PubMed1980

Assembly of subcomponents C1r and C1s of first component of complement: electron microscopic and ultracentrifugal studies.

Monomeric C1s (Mr, 85,000; s20,w, 4.3S), a subcomponent of first component of complement (C1), the dimer (Mr, 170,000; s20,w, 6.7 S) of C1r, another subcomponent, and the tetrameric complex (C1r,C1s)2 (Mr, 340,000; s20,w, 8.7 S) are elongated molecules. Hydrodynamic equivalents of cylindrical shape have a diameter of 3.3 nm and lengths of 20 nm for C1s, 36 nm for (C1r)2, and 64 nm for (C1r,C1s)2. In electron micrographs the C1r,C1s complex appears as a chain composed of six to eight globular domains with a contour length of 51 nm. A structure is proposed in which (C1r)2 forms a core to which C1s protomers are associated at both ends. The C1 complex (s20,w, 16.3 S) reconstituted from C1q, C1r, and C1s dissociates under the conditions used for electron microscopy. Some features of the C1 complex are revealed in the dissociation products.

Centrifugation, Density Gradient↗
PubMed1985

Atypical hypocomplementemic vasculitis syndrome in a child.

We report a patient who developed recurrent urticaria and angioedema at age 2 years, severe hypocomplementemic glomerulonephritis at 11 years, and end-stage renal disease at 14 years. His disease resembled the hypocomplementemic vasculitis syndrome but was atypical in its early age of presentation, severe hypocomplementemia, and progression to end-stage renal disease. Serum C1q levels were extremely low, and C4, C2, C3, and C5 levels were significantly reduced. Serum C1 inhibitor (C1INH) levels were slightly low, presumably from consumption. Circulating C1INH-C1r-C1s complexes were evidenced by reduced ratios of functional to antigenic C1INH and antigenic C1r to C1s. Family members had normal functional and antigenic levels of all complement components studied. The patient's serum, erythrocytes, platelets, and mononuclear cells did not activate complement when mixed with normal target serum. Absence of a circulating complement activator and the low serum C3 and C5 levels suggested the presence of a solid-phase complement activator, possibly related to renal or systemic vascular endothelium. As in patients with homozygous deficiencies of classical pathway components, a severe, prolonged, acquired C1q deficiency may have predisposed this patient to the development of glomerulonephritis.

Angioedema↗
PubMed1995

Analysis of the N-linked oligosaccharides of human C1s using electrospray ionisation mass spectrometry.

Information on the structures of the oligosaccharides linked to Asn residues 159 and 391 of the human complement protease C1s was obtained using mass spectrometric and monosaccharide analyses. Asn159 is linked to a complex-type biantennary, bisialylated oligosaccharide NeuAc2 Gal2 GlcNAc4 Man3 (molecular mass = 2206 +/- 1). Asn391 is occupied by either a biantennary, bisialylated oligosaccharide, or a triantennary, trisialylated species NeuAc3 Gal3 GlcNAc5 Man3 (molecular mass = 2861 +/- 1), or a fucosylated triatennary, trisialylated species NeuAc3 Gal3 GlcNAc5 Man3 Fuc1 (molecular mass = 3007 +/- 1), in relative proportions of approximately 1:1:1. The carbohydrate heterogeneity at Asn391 gives rise to three major types of C1s molecules of molecular masses 79,318 +/- 8 (A), 79,971 +/- 8 (B), and 80,131 +/- 8 (C), with an average mass of 79,807 +/- 8. A minor modification, yielding an extra mass of 132 +/- 2, is also detected within positions 1-153.

Asparagine↗
PubMed1988

Expression of functional human C1 inhibitor in COS cells.

Full length human C1 inhibitor cDNA was cloned into a vector suitable for transient expression in COS-1 cells. Transfected COS cells secreted an immunoreactive protein of Mr approximately 110,000 that appeared to be functionally equivalent to the plasma-derived protein as established by the following criteria: 1) ability to form sodium dodecyl sulfate-stable complexes with C1s, factor XIIa, and kallikrein; 2) inhibition of C1s-mediated C4 consumption; and 3) susceptibility to inactivation by the nontarget proteinase elastase. Quantitation of secreted recombinant C1 inhibitor by radioimmunoassay indicated that 72 h after transfection the level was approximately 2.2 micrograms/ml. Treatment of transfected cells with tunicamycin resulted in secretion of a protein of Mr approximately 90,000 that was also capable of complex formation with C1s.

Animals↗
PubMed1987

Concentrations of C1q, factor B, factor D and properdin in healthy children, and the age-related presence of circulating C1r-C1s complexes.

The concentrations of C1q, factor B, factor D and properdin were determined in healthy children belonging to various age groups of one through five years of age. All concentrations were found to be age-dependent, though they varied from one component to another with regard to ontogenetic pattern. Thus, the concentrations of factor B were high, and those of factor D low throughout the age range studied. C1q and properdin levels were lowest in the younger children, who also showed a fairly high incidence of C1r-C1s complexes in excess of C1q. Since the concentrations of C1q are influenced by those of IgG, the presence of C1r-C1s complexes might partly have reflected maturation of immunoglobulin synthesis during ontogeny.

Age Factors↗
PubMed1984

Comparative study of the fluid-phase proteolytic cleavage of human complement subcomponents C4 and C2 by C1s and C1r2-C1s2.

The C3 convertase of the classical pathway of complement is composed of fragments C4b and C2a resulting from cleavage of C4 and C2 by activated C1. The limited proteolysis of these two different substrates by the same protease, C1s, has been studied in the fluid phase using purified proteins. The turnover numbers of C2 and C4 cleavage by C1s were affected to different extents, depending on whether C1s was alone or associated with C1r or with monoclonal antibodies to C1s. The binding of C2 to C4 favours the proteolysis of C2 by C1s, as revealed by the use of I2-treated C2.

Antibodies, Monoclonal↗
PubMed1994

A 100-kDa protein in the C4-activating component of Ra-reactive factor is a new serine protease having module organization similar to C1r and C1s.

Ra-reactive factor (RaRF), a C-dependent bactericidal factor in mice, is composed of one polysaccharide-binding component and one C4/C2-activating component. The former is an oligomer of 28-kDa protein corresponding to the mannose-binding protein of mice. The 100-kDa protein, P100, has been shown to be present in the C4/C2-activating component. This protein generates 29- and 70-kDa polypeptide chains when reduced. In this study, we determined the nucleotide sequence of cDNA coding for P100. cDNAs were prepared by reverse transcription PCR and cassette-ligation-mediated PCR on mRNA from BALB/c mouse liver, using primers synthesized by reference to the sequence determined in a previous study. The results of cDNA sequencing indicate that the precursor protein of P100 containing a 24-residue signal peptide consists of 704 amino acid residues. Taking the results of the previous electrophoretic study into consideration, it is thought that the cleavage of mature P100 protein generates a 29-kDa chain of 251 residues and a 70-kDa chain of 429 residues. Although homology in the amino acid sequence of P100 with that of human C1r and C1s subcomponents of C was less than 40%, a striking similarity in domain organization was found among these proteins, indicating that P100 is a new C4-activating serine protease structurally similar to C1r and C1s. Northern hybridization showed that the liver was the primary site of the expression of the P100 gene.

Amino Acid Sequence↗