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PubMed1980

Inhibition of immune complex-mediated activation of complement. Effects of agents modulating activation of, and the activated C1 complex.

Several known chemical compounds were shown to selectively inhibit the interaction between immune aggregates and C1q, the activation of C1r-C1s complex by immune aggregate-bound C1q, and the esterolytic activity of the activated C1s, C1s. These reactions are relevant to the functions of the first complement component, C1, and its activation induced by immune complexes. The effects of these inhibitors on tissue injury mediated by immune complex-induced complement activation, such as immune hemolysis, passive cutaneous anaphylaxis, and experimental glomerulonephritis were examined. The results suggest an approximate correlation between the activity shown on the molecular level and that obtained in vivo. One such compound, suramin, was shown to be an effective inhibitor of PCA and the proteinuria manifestation of EGN while not affecting antibody fixation to tissue or histamine-mediated skin reaction. These results suggest that effective suppression of the initial steps of complement activation may be of value of controlling immune complex-mediated tissue injuries in disease.

Animals↗
PubMed1991

The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors.

The A5 antigen is a neuronal cell surface protein of Xenopus presumed to be involved in the neuronal recognition between the optic nerve fibers and the visual centers. Analyses of cDNA clones revealed that the A5 antigen is a class I membrane protein containing two different internal repeats in the extracellular segment. The first repeat bears homology to domain III of complement components C1r and C1s, and the second repeat is homologous to the C1 and C2 domains of coagulation factors V and VIII. The mRNA for the A5 antigen was present in retinal ganglion cells and visual center neurons. Nonneuronal cells in the peripheral and central nervous systems did not express the mRNA for the A5 antigen.

Amino Acid Sequence↗
PubMed2006

Synthesis of complement proteins in the human chorion is differentially regulated by cytokines.

The aim of the current paper was to determine the chorion's contribution to complement synthesis in the placenta and its regulation by cytokines. Biosynthetic labeling followed by immunoprecipitation with polyclonal antibodies was performed in chorionic tissue and chorion-derived cells. Eight complement proteins, factor B, C3, C1r, C1s, C1 inhibitor, factor H, C4 and C2 were detected in chorionic tissue and were secreted extracellularly. In chorion-derived cells, IL-1beta stimulated factor B synthesis but had no effect on C1r, C1 inhibitor, C1s, factor H and C4. TNFalpha had no stimulative effect on any of the complement proteins tested. In contrast, both IL-1beta and TNFalpha highly induced IL-6 secretion in chorion-derived cells, demonstrating the overall responsiveness of these cells to these stimuli. Interestingly, IFN-gamma increased the synthesis of C1s, C1r, C1 inhibitor, C4 and factor H in chorion-derived cells. The fact that the latter two complement proteins have opposing effects on immune activation of the complement cascade demonstrates the complex balance required to both maintain an ability to ward off infections but simultaneously suppress the immune response to enable tolerance of the allograft fetus.

Cells, Cultured↗
PubMed2005

Structural comparison of human C4A3 and C4B1 after proteolytic activation by C1s.

The fourth component of human complement is an essential part of the classical and lectin pathways performing multifunctional roles in both host defense and immune regulation. C4 is the most polymorphic member of the complement proteins, and complete deficiency is strongly associated with autoimmune disease, especially, systemic lupus erythematosus (SLE). Of the two C4 genes C4A, but not C4B, null alleles have been implicated as important independent disease susceptibility genes occurring in more than half of SLE patients. Whether and how this deficiency contributes to the development or pathology remains unclear. We do know that activation of C4 by C1s cleaves the thioester bond, thus inducing a conformational change that exposes numerous ligand-binding sites involved in functional activity. Structural comparison, among many other tools, plays an important role in predicting function. In this report, the tertiary structures of C4A and C4B were compared using near and far-UV circular dichroism, ANS fluorescence, site-specific monoclonal antibodies and isoelectric focusing. Negligible differences in the native proteins were found. However, the activated proteins were dissimilar in secondary and tertiary structure that was accompanied by significant differences in charge distribution and surface hydrophobicity. These conformational differences, together with known acceptor preferences, have functional implications for the association between C4A null alleles and SLE.

Alleles↗
PubMed1986

Purification, identification and characterization of chicken C1q, a subcomponent of the first component of complement.

A component, having the equivalent haemolytic activity to that of human complement subcomponent C1q, was purified by a combination of precipitation with EGTA, gel filtration, ion exchange and adsorption chromatography from chicken serum. Yields ranged from 8 to 15 mg/litre of serum. The finally purified preparation generates full Cl haemolytic activity when assayed with human complement subcomponents C1r and C1s, and have been identified as chicken C1q. The molecular weight of undissociated C1q, as estimated on polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate (SDS), is 504,000. Under dissociating but non-reducing conditions, the C1q was shown to consist of 2 subunits having molecular weights of 52,700 and 51,200 in a molar ratio of 2:1. On reduction, the 52,700 molecular weight subunit gave chains with molecular weights of 25,900 and 24,800 in equimolar ratio, and the 51,200 molecular weight subunit decreased to 24,800. The C1q contains hydroxyproline, hydroxylysine, a high percentage of glycine and approximately 7% carbohydrate. Collagenase digestion of C1q caused a rapid loss of haemolytic activity and produced much smaller peptide fragments.

Amino Acids↗
PubMed1982

Structural features of the first component of human complement, C1, as revealed by surface iodination.

Lactoperoxidase-catalysed surface iodination and sucrose-gradient ultracentrifugation were used to investigate the structure of human complement component C1. 1. Proenzymic subcomponents C1r and C1s associated to form a trimeric C1r2-C1s complex (7.6 S) in the presence of EDTA, and a tetrameric Clr2-C1s2 complex (9.1 S) in the presence of Ca2+. Iodination of the 9.1 S complex led to a predominant labelling of C1r (70%) over C1s (30%), essentially located in the b-chain moiety of C1r and in the a-chain moiety of C1s. 2. Reconstruction of proenzymic soluble C1 (15.2 S) from C1q, C1r and C1s was partially inhibited when C1s labelled in its monomeric form was used and almost abolished when iodinated C1r was used. Reconstruction of fully activated C1 was not possible, whereas hybrid C1q-C1r2-C1s2 complex was obtained. 3. Iodination of proenzymic or activated C1 bound to IgG-ovalbumin aggregates led to an equal distribution of the radioactivity between C1q and C1r2-C1s2. With regard to C1q, the label distribution between the three chains was similar whether C1 was in its proenzymic or activated form. Label distribution in the C1r2-C1s2 moiety of C1 was the same as that obtained for isolated C1r2-C1s2, and this was also true for the corresponding activated components. However, two different labelling patterns were found, corresponding to the proenzyme and the activated states.

Centrifugation, Density Gradient↗
PubMed1987

The superfamily of C3b/C4b-binding proteins.

The determination of primary structures by amino acid and nucleotide sequencing for the C3b-and/or C4b-binding proteins H, C4BP, CR1, B, and C2 has revealed the presence of a common structural element. This element is approximately 60 amino acids long and is repeated in a tandem fashion, commencing at the amino-terminal end of each molecule. Two other complement components, C1r and C1s, have two of these repeating units in the carboxy-terminal region of their noncatalytic A chains. Three noncomplement proteins, beta 2-glycoprotein I (beta 2I), the interleukin 2 receptor (IL 2 receptor), and the b chain of factor XIII, have 4, 2 and 10 of these repeating units, respectively. These proteins obviously belong to the above family, although there is no evidence that they interact with C3b and/or C4b. Human haptoglobin and rat leukocyte common antigen also contain two and three repeating units, respectively, which have more limited homology with the repetitive regions in this family. All available data indicate that multiple gene duplications and exon shuffling have been important features in the divergence of this family of proteins with the 60-amino-acid repeat.

Amino Acid Sequence↗
PubMed1987

Interactions of purified Serratia marcescens metalloproteases with fresh human serum and with purified human serum proteins.

Exposure of fresh human serum to two purified metalloproteases of S. marcescens strains SF 178 and SH 186 (both of serotype O6/O14:H12) at 35 degrees C, 3 h, resulted in altered electrophoretic mobility of the protease inhibitors alpha 1-antitrypsin and alpha 2-macroglobulin, alpha 2-HS-glycoprotein, and complement (C) components C1q, C1s, C3a, C3c, C4, C5, and C9, but not C6, C7, C8, and properdin, as determined with electroimmunoassays (Laurell technique). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the partial degradation of the heavy (H) chain of purified human immunoglobulin IgG by the metalloproteases of S. marcescens strains SF 178 and SV O1 (serotype O13/O19:H1), but not by the metalloproteases of strains SH 186 and SE 182 (serotype O9B:H11) following extended incubation (35 degrees C, 22 h). Human IgA and IgM were refractory. Purified human C components, C3, C4, C5, C6, C7, C8, and C9, as well as purified human alpha 1-antitrypsin, alpha 2-macroglobulin, transferrin, and lactoferrin were attacked by the S. marcescens metalloproteases SF 178 and SH 186 at 35 degrees C for 5 h, as demonstrated with the SDS-PAGE procedure; haptoglobin and C-reactive protein were resistant.

Acute-Phase Proteins↗
PubMed1978

Haemolytic complement in peripheral lymph of normal men.

The haemolytic activity of nine individual components of complement and the concentrations of C1q, C1s, C4, C3, C3PA and C9 proteins were measured in the leg lymph and serum of four normal men. The mean lymph/serum ratio for total haemolytic complement was 0.257, for C1H50 it was 0.138, for C4H50 0.105, for C2H50 0.279, for C3H50 0.063, for C5H50 0.266, for C6H50 0.145, for C7H50 0.25, for C8H50 0.244 and for C9H50 0.253. The mean lymph/serum ratio for complement proteins was: for C1q 0.048, for C1s 0.06, for C4 0.199, for C3 0.225, for C9 0.244 and for C3PA 0.263. The low haemolytic activity of total complement and of all components in lymph seems to be dependent on the low complement protein concentration. The remarkably low lymph C1q protein concentration may play a physiological role in controlling total complement activity in lymph and interstitial fluid. The total complement haemolytic activity in lymph exceeded the haemolytic activity of C1 and C3, which may indicate the possibility of independent activation of C5-7 and C8-9. The considerably low C3H50 level, with high C3 protein concentration, at present lacks a proper explanation.

Adolescent↗
PubMed1989

Deficiency of the first component of human complement.

C1 deficiency results from an absence or lowering of the level of one or more of the proteins C1q, C1r and C1s, which are the subcomponents of the C1 complex of the classical pathway of the serum complement system. The major clinical pattern shown in such deficiency states is an inability to deal effectively with immune complexes, resulting in the typical symptoms associated with immune-complex-related diseases and a great susceptibility to recurrent bacterial infections. Both acquired and genetic deficiencies of the C1 subcomponents have been reported; the possible genetic deficiencies appear quite rare, with only 14 reports of C1q deficiency (involving 24 people) and six reports of C1r/C1s deficiency (involving 11 people) appearing in the literature to date.

Complement Activation↗
PubMed1994

Two domains of the tolloid protein contribute to its unusual genetic interaction with decapentaplegic.

The zygotic dorsal-ventral patterning gene tolloid (tld) exhibits a complex structure consisting of an N-terminal domain with sequence similarity to the astacin family of metalloproteases and a C-terminal domain composed of two EGF-like repeats and five copies of the CUB repeat which was first found in human complement proteins C1r and C1s. The overall structure of TLD is similar to the human bone morphogenetic protein, BMP-1. Previous genetic studies (Ferguson and Anderson, 1992) have shown that certain tld alleles behave antagonistically toward decapentaplegic (dpp), a second zygotic dorsal-ventral patterning gene whose product is most closely related to the TGF-beta superfamily members BMP-2 and BMP-4. The common phenotype and genetic interaction data may suggest a direct physical association between these two proteins. In this study, we use an allelic series of haplo-viable dpp mutations to order the strength of the tld antagonistic interaction. In addition, we have identified the lesions associated with 20 tld mutations by DNA sequencing. These mutations consist of six alleles that behave in an antimorphic manner with respect to dpp, five alleles that revert the antagonistic interaction, and 9 loss-of-function alleles with a range of phenotypes from weak to strong. We find that antimorphic mutations and second-site revertants cluster to the protease domain and to a second site located at the junction of the first two CUB repeats. In contrast, loss-of-function mutations are dispersed throughout the length of the protein. Those mutations that map within the CUB repeats invariably affect consensus residues, thereby establishing the functional significance of certain residues in the CUB repeat consensus sequence. Possible molecular models for TLD action are discussed.

Alleles↗
PubMed1994

Characterization of tolloid-related-1: a BMP-1-like product that is required during larval and pupal stages of Drosophila development.

The Drosophila tolloid (tld) gene product belongs to a family of developmentally important proteins that includes bone morphogenetic protein-1 (BMP-1). In Drosophila, tld is required at the blastoderm stage to establish pattern within the dorsal half of the embryo. Genetic analysis suggests that the major function of tld is to augment the activity of the decapentaplegic gene product, a close relative of the TGF-beta superfamily members, BMP-2 and BMP-4. In this report, we describe a new gene called tolloid-related-1 (tlr-1) that maps immediately proximal to tld. Sequence analysis indicates that tlr-1 has a large N-terminal extension relative to tld, but otherwise shows the same general organization of sequence motifs found in tld and other BMP-1 family members. These include a region of similarity to astacin, a crayfish metalloprotease, five copies of a repeat first found in complement proteins C1r and C1s, and two copies of an epidermal growth factor-like sequence. In situ hybridization experiments show that tlr-1 expression partially overlaps tld expression in early embryos, but shows unique transcriptional patterns in late stage embryos that are not seen with tld. In larval stages, both genes are expressed in identical patterns in imaginal discs and in the optic lobes of the brain, but tlr-1 is more abundant than tld. Deletions that eliminate tlr-1 expression cause lethality during larval and pupal stages of development. A small proportion of homozygous mutant flies eclose and show wing veination defects. Transgenic animals in which a tlr-1 cDNA is driven by the tld promoter fail to rescue tld mutations, and extra copies of tld fail to rescue tlr-1 mutations, implying that these genes have evolved functionally distinct features. We propose that tld and tlr-1 arose by gene duplication and that each has evolved independently to acquire distinct tissue specific roles in Drosophila development.

Amino Acid Sequence↗
PubMed1991

The Drosophila dorsal-ventral patterning gene tolloid is related to human bone morphogenetic protein 1.

Mutations in the Drosophila tolloid (tld) gene lead to a partial transformation of dorsal ectoderm into ventral ectoderm. The null phenotype of tld is similar to, but less severe than decapentaplegic (dpp), a TGF-beta family member required for the formation of all dorsal structures. We have cloned the tld locus by P element tagging. At the blastoderm stage, tld RNA is expressed dorsally, similar to that described for dpp. Analysis of a tld cDNA reveals three sequence motifs: an N terminal region of similarity to a metalloprotease, two EGF-like repeats, and five copies of a repeat found in human complement proteins C1r and C1s. tld sequence is 41% identical to human bone morphogenetic protein 1 (BMP-1); the closest members to dpp within the TGF-beta superfamily are BMP-2 and BMP-4, two other bone morphogenetic proteins. These findings suggest that these genes are members of a signal generating pathway that has been conserved between insects and mammals.

Amino Acid Sequence↗
PubMed2006

The interaction of recombinant subdomains of the procollagen C-proteinase with procollagen I provides a quantitative explanation for functional differences between the two splice variants, mammalian tolloid and bone morphogenetic protein 1.

The procollagen C-proteinase (PCP) is a zinc peptidase of the astacin family and the metzincin superfamily. The enzyme removes the C-terminal propeptides of fibrillar procollagens and activates other matrix proteins. Besides its catalytic protease domain, the procollagen C-proteinase contains several C-terminal CUB modules (named after complement factors C1r and C1s, the sea urchin UEGF protein, and BMP-1) and EGF-like domains. The two major splice forms of the C-proteinase differ in their overall domain composition. The longer variant, termed mammalian tolloid (mTld, i.e., PCP-2), has the protease-CUB1-CUB2-EGF1-CUB3-EGF2-CUB4-CUB5 composition, whereas the shorter form termed bone morphogenetic protein 1 (BMP-1, i.e., PCP-1) ends after the CUB3 domain. Two related genes encode proteases similar to mTld in humans and have been termed mammalian tolloid like-1 and -2 (mTll-1 and mTll-2, respectively). For mTll-1, it has been shown that it has C-proteinase activity. We demonstrate that recombinant EGF1-CUB3, CUB3, CUB3-EGF2, EGF2-CUB4, and CUB4-CUB5 modules of the procollagen C-proteinase can be expressed in bacteria and adopt a functional antiparallel beta-sheet conformation. As shown by surface plasmon resonance analysis, the modules bind to procollagen I in a 1:1 stoichiometry with dissociation constants (K(D)) ranging from 622.0 to 1.0 nM. Their binding to mature collagen I is weaker by at least 1 order of magnitude. Constructs containing EGF domains bind more strongly than those consisting of CUB domains only. This suggests that a combination of CUB and EGF domains serves as the minimal functional unit. The binding affinities of the EGF-containing modules for procollagen increase in the order EGF1-CUB3 < CUB3-EGF2 < EGF2-CUB4. In the context of the full length PCP, this implies that a given module has an affinity that continues to increase the more C-terminally the module is located within the PCP. The tightest binding module, EGF2-CUB4 (K(D) = 1.0 nM), is only present in mTld, which might provide a quantitative explanation for the different efficiencies of BMP-1 and mTld in procollagen C-proteinase activity.

Animals↗
PubMed1992

Slp is an essential component of an EDTA-resistant activation pathway of mouse complement.

Slp (sex-limited protein) is a mouse serum protein encoded by a major histocompatibility complex class III gene. It is considered to be a product of a duplicated complement component C4 gene, but without functional activity. Originally it has been found expressed only in adult males with the S region of the H-2d or H-2s haplotype. In this report we present evidence that Slp is involved in a form of mouse complement activation that occurs after fractionation of serum by polyethylene glycol precipitation. This activation pathway is EDTA-resistant (i.e., independent of classical and alternative pathway activation), is regulated by C1 inhibitor, and leads to the generation of hemolytically active membrane attack complexes. A positive correlation between this EDTA-resistant mouse complement activity and reported Slp levels was found. Direct evidence for a functional role of Slp came from substitution experiments in which purified Slp induced hemolytic activity in polyethylene glycol-fractionated, Slp-deficient mouse serum. Selective depletion of other complement components suggested a role for C1s-, C2, and C5, but not C3, in the Slp-dependent complement activation. A model for this type of mouse complement activation is presented.

Aging↗
PubMed1994

Enterokinase, the initiator of intestinal digestion, is a mosaic protease composed of a distinctive assortment of domains.

Enterokinase is a protease of the intestinal brush border that specifically cleaves the acidic propeptide from trypsinogen to yield active trypsin. This cleavage initiates a cascade of proteolytic reactions leading to the activation of many pancreatic zymogens. The full-length cDNA sequence for bovine enterokinase and partial cDNA sequence for human enterokinase were determined. The deduced amino acid sequences indicate that active two-chain enterokinase is derived from a single-chain precursor. Membrane association may be mediated by a potential signal-anchor sequence near the amino terminus. The amino terminus of bovine enterokinase also meets the known sequence requirements for protein N-myristoylation. The amino-terminal heavy chain contains domains that are homologous to segments of the low density lipoprotein receptor, complement components C1r and C1s, the macrophage scavenger receptor, and a recently described motif shared by the metalloprotease meprin and the Xenopus A5 neuronal recognition protein. The carboxyl-terminal light chain is homologous to the trypsin-like serine proteases. Thus, enterokinase is a mosaic protein with a complex evolutionary history. The amino acid sequence surrounding the amino terminus of the enterokinase light chain is ITPK-IVGG (human) or VSPK-IVGG (bovine), suggesting that single-chain enterokinase is activated by an unidentified trypsin-like protease that cleaves the indicated Lys-Ile bond. Therefore, enterokinase may not be the "first" enzyme of the intestinal digestive hydrolase cascade. The specificity of enterokinase for the DDDDK-I sequence of trypsinogen may be explained by complementary basic-amino acid residues clustered in potential S2-S5 subsites.

Amino Acid Sequence↗
PubMed1999

Molecular cloning of cDNA for matriptase, a matrix-degrading serine protease with trypsin-like activity.

A major protease from human breast cancer cells was previously detected by gelatin zymography and proposed to play a role in breast cancer invasion and metastasis. To structurally characterize the enzyme, we isolated a cDNA encoding the protease. Analysis of the cDNA reveals three sequence motifs: a carboxyl-terminal region with similarity to the trypsin-like serine proteases, four tandem cysteine-rich repeats homologous to the low density lipoprotein receptor, and two copies of tandem repeats originally found in the complement subcomponents C1r and C1s. By comparison with other serine proteases, the active-site triad was identified as His-484, Asp-539, and Ser-633. The protease contains a characteristic Arg-Val-Val-Gly-Gly motif that may serve as a proteolytic activation site. The bottom of the substrate specificity pocket was identified to be Asp-627 by comparison with other trypsin-like serine proteases. In addition, this protease exhibits trypsin-like activity as defined by cleavage of synthetic substrates with Arg or Lys as the P1 site. Thus, the protease is a mosaic protein with broad spectrum cleavage activity and two potential regulatory modules. Given its ability to degrade extracellular matrix and its trypsin-like activity, the name matriptase is proposed for the protease.

Amino Acid Sequence↗
PubMed1995

alpha 2-Macroglobulin binds to and inhibits mannose-binding protein-associated serine protease.

We determined the presence in human serum of a complex consisting of mannose-binding protein (MBP), MBP-associated serine protease (MASP), which is a C1s-like protein with complement activation activity, and alpha 2-macroglobulin (alpha 2M). Binding between these three molecules was in an ascending order of MBP, MASP and alpha 2M, in that alpha 2M bound directly to MASP, possibly through covalent bonds, whereas the binding between MBP and MASP was reversible and Ca(2+)-dependent. Since it was found that alpha 2M can inhibit complement activation by MASP and that MASP in the complex lacks esterolytic activity, it is conceivable that alpha 2M plays a regulatory role in MBP-derived complement activation via a mechanism involving MASP (the lectin pathway).

Calcium↗