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PubMed1987

Subunit interactions in the first component of complement, C1.

Interactions between C1q and other subunits of C1 were analyzed by sucrose gradient ultracentrifugation. A zone of dilute, radioiodine labelled C1q was sedimented through uniform concentrations of either C1r2C1s2, C1r2, C1r2 or C1s(2). The dissociation constants were found to be 3 x 10(-9) M and 6 x 10(-9) M for C1r2C1s2 and C1r2 binding respectively. Hill coefficients of 1 indicated no cooperativity in these bindings. Positive cooperativity was found in binding of C1s to C1q. Dissociation constants of 2 x 10(-6) M and 5 x 10(-8) M were obtained form computer modelling of a two step binding mechanism. No interaction was detected between C1q and activated C1r2. The data indicate that most of the interactions between C1q and C1r2C1s2 originates from a strong binding to the C1r2 moiety of the zymogen complex. This interaction is lost upon activation of C1r2.

Binding Sites↗
PubMed1984

Neutron scattering studies of subcomponent C1q of first component C1 of human complement and its association with subunit C1r2C1s2 within C1.

Neutron scattering studies are reported on subcomponent C1q of component C1 of human complement, and on C1, the complex of C1q with subunit C1r2C1s2. For C1q, the molecular weight was determined as 460,000. The radius of gyration at infinite contrast RC is 12.8 nm. The RC values for the proteolytically cleaved forms of C1q, namely the heads and the stalks, are 1.5 to 2 nm and 11 nm, respectively, and thus the axis-to-arm angle of C1q is estimated at 45 degrees. Neutron data for subunit C1r2C1s2 are published elsewhere. The neutron data on C1 lead to an RC value of 12.6 nm for proenzymic C1 and a molecular weight of 820,000. The wide-angle scattering curve of C1q exhibits a minimum at Q = 0.28 nm-1 and a maximum at 0.39 nm-1; on the addition of C1r2C1s2, this minimum disappears. The neutron data on C1 indicate that C1q and C1r2C1s2 have complexed with a large conformational change in one or both parts. No conformational changes can be detected on the activation of C1 by this method.

Complement Activating Enzymes↗
PubMed1988

Complement activation occurs through both classical and alternative pathways prior to onset and resolution of adult respiratory distress syndrome.

We have previously reported that plasma concentrations of the terminal complement (C) complex (TCC), C5b-9, increased significantly 2 days prior to onset of adult respiratory distress syndrome (ARDS) and also 1 day preceding its resolution. To determine the pathway of complement activation that preceded development and resolution of this acute inflammatory lung injury in septic patients, we quantified the C1rC1s-C1 inhibitor complex and the C3bP complex, which are generated following activation of classical and alternative complement pathways, respectively. Two days prior to diagnosis of ARDS, the plasma C1rC1s-C1 inhibitor complex and C3bP complex levels increased 22 and 14%, respectively. Furthermore, significant correlations were identified between concentrations of the TCC and C1rC1s-C1 inhibitor complex (r = 0.73, P = 0.003) and also with the levels of the TCC and C3bP complex (r = 0.81, P = 0.002) before onset of ARDS. Equally of interest, the C1rC1s-C1 inhibitor complex and C3bP complex concentrations increased 68 and 35%, respectively, 1 day before resolution of ARDS. Similarly, significant elevations of TCC concentrations preceding resolution of ARDS correlated with C1rC1s-C1 inhibitor complex (r = 0.66, P = 0.02) and also with C3bP complex (r = 0.72, P = 0.002) levels. Our results indicate that both the classical and alternative complement pathways are activated prior to onset of ARDS and also before its resolution in septic patients.

Complement Activating Enzymes↗
PubMed1982

The binding and activation of the Clr-Cls subunit of the first component of human complement.

The value of the functional affinity constant between 125I-labelled Clq and the Clr-Cls tetramer (when free in solution) in the formation of Cl was found to be 3.6 X 10(7) M-1. When Clq was bound to activating immune complexes, the value of K was about 10-fold higher before initiation of activation and there was a further two to three-fold rise as activation proceeded. The addition of an excess of unlabelled Clq increased the rate of activation of 125I-labelled Cl, suggesting an interaction between Clr-Cls and two neighbouring Clq molecules. It is suggested that the tetramer Clr-Cls may bind bivalently to Clq when free in solution, but on binding to activating complexes, one of the Clr-Cls binding sites is detached from Clq and becomes bound to a site on the complex. The resultant spatial rearrangement of the Clr molecules within the tetramer may be optimal for autocatalytic activation of Clr.

Antigen-Antibody Complex↗
PubMed1982

Kinetics of activation of the first component of complement (C1) by IgG oligomers.

The rate of activation of the first component of complement, Cl, by IgG oligomers was investigated. The kinetics of Clr activation exhibited a pronounced lag phase at low IgG concentration and were followed by a rapid conversion of the proenzyme Cls to Cls. Activation of Cl resulted in a conformational change of this complex. Bases on these results, a model of Cl activation by IgG oligomers is proposed: The efficiency of Cl activation by IgG oligomers is in parallel to their binding affinity to Clq. Clr undergoes a slow rearrangement to a conformation which is not stable and is autoactivated, then Clr rapidly converts Cls to Cls.

Antigen-Antibody Complex↗
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↗
PubMed1983

Measurement of the association constants of the complexes formed between intact C1q or pepsin-treated C1q stalks and the unactivated or activated C1r2C1s2 tetramers.

The association constants between C1q and C1r2C1s2 and between C1q and C1r2C1s2 were measured in solution using a new technique which employs sucrose gradient ultracentrifugation to estimate thermodynamic association constants. In this technique, zones of dilute, radioiodine-labeled C1q were sedimented through uniform concentrations of either C1r2C1s2 or C1r2C1s2. The zones remained intact, indicating that the dynamic equilibrium was rapid compared with the time of centrifugation. The observed increases in the sedimentation coefficients of the C1q zones were assumed to be directly proportional to the fraction of C1q bound in the dynamic equilibrium. Binding curves were constructed by performing the measurements at many C1r2C1s2 and C1r2C1s2 concentrations. The association constants were estimated from the midpoints of the binding curves and found to be 6.7 X 10(7)M-1 for C1r2C1s2 binding to 125I-C1q. After activation of the C1r2C1s2 the association constant decreased 10-fold to 7.1 X 10(6)M-1. These association constants refer to solvent conditions of pH 7.35, 1 mM Tris, 5 mM Ca2+ and 150 mM NaC1, pH 7.35. Similar measurements were performed with the collagenous peptic fragment of C1q and both 125I-C1r2C1s2 and 125I-C1r2C1s2. The association constants were independent of the state of activation and both found to be about 2 X 10(7) M-1, suggesting that most if not all of the interactions between C1q and C1r2C1s2 were confined to the collagenous portion of C1q.

Binding Sites↗
PubMed1985

Co-operative interaction of subcomponents of the first component of complement with IgG: a functional defect of dimeric Facb from rabbit IgG.

By following dissociation kinetics of radiolabelled C1q from rabbit IgG antibody-sensitized sheep red blood cells (SRBC) before and after its incorporation in the C1 complex, it was demonstrated that the binding stability is markedly enhanced by the presence of the C1r2-C1s2 subunit of C1 which by itself exhibits no significant binding capacity to immune complexes. The dissociation of C1q was decreased by up to 95%, the extent of decrease being pronounced as the cell surface IgG antibody density increased. However, such a stabilizing effect of C1r2-C1s2 was largely abolished when SRBC sensitized with the dimeric fragment F(acb)2 lacking C gamma 3 was used as the C1 binder, whereas the dissociation rate of uncomplexed C1q from F(acb)2-sensitized cells was similar to that from whole IgG-sensitized cells. It was also shown that, although the C1r2-C1s2 subunit is dissociated selectively from C1 bound to either IgG- or F(acb)2-sensitized cells in the presence of EDTA, it is held on much longer by the former cells than the latter cells. These results were taken to indicate that, although the C1 fixation by immune complexes of IgG is undertaken primarily by the interaction between C1q and the C gamma 2 domain, it is also strengthened by the secondary interaction between the C1r2-C1s2 subunit of C1 and the C gamma 3 domain or a structure which is dependent on the pair of C gamma 3 domains.

Animals↗
PubMed1985

Nature of the interaction between the C1q and C1r2S2 subunits of the first component of human complement.

The strength of interaction between the C1q and C1r2S2 subunits of C1 was studied as a function of temp. During centrifugation through sucrose density gradients at 4 degrees C, macromolecular C1 readily dissociated as it sedimented away from its free subunits. In contrast, at 20 degrees C, C1 remained associated as the 16S complex throughout centrifugation, thus indicating a stronger interaction between C1q and C1r2S2 at the higher temp. C1-inhibitor (C1-In) or nitrophenylguanidinobenzoate was present during centrifugation to prevent C1 activation. That native C1 was in fact the species being studied was confirmed by SDS-PAGE analysis. To investigate this temp dependence without using inhibitors, an alternative approach was used. Trace amounts of 125I-C1q were centrifuged through numerous sucrose density gradients, each of which contained a different concn of native C1r2S2 throughout the gradient. The s-rate of 125I-C1q increased with increasing C1r2S2 input. An association constant of 4.9 X 10(7) M-1 was calculated for this reversible interaction at 4 degrees C. However, at 20 degrees C, the data indicated a much higher affinity reaction since the addition of far less C1r2S2 was required for the s-rate of 125I-C1q to reach the 16S plateau. The presence of Cl-In did not affect these results. We have demonstrated that the association of C1q with C1r2S2 increases with increasing temp, a finding suggestive of a hydrophobic interaction. However, since we also show that C1 readily dissociates with increasing NaCl concn, the C1q-C1r2S2 interaction must, in fact, be ionic in nature. We therefore conclude that the temp dependence of the inter-subunit interaction is the result of a conformational change(s) within one of the subunits, and propose that this change may be similar to that occurring during Cl activation.

Centrifugation, Density Gradient↗
PubMed1988

Guinea pig macrophages synthesize a low molecular weight form of C1q with affinity for the C1r2C1s2-complex but which does not bind to Fc in immunoglobulin aggregates.

Biosynthetically labelled C1q secreted by guinea pig peritoneal macrophages was analysed by sedimentation through sucrose gradients followed by SDS-PAGE. In addition to the haemolytically active C1q of mol. wt 460,000 Da a low mol. wt (LMW) form of C1q was identified which had no detectable affinity for Fc of aggregated immunoglobulin, but which retained the ability to associate with the C1r2s2-complex. This LMW-C1q was covalently associated with two additional polypeptides of mol. wt 46 and 50 kDa.

Animals↗
PubMedDate not supplied

Mannan-binding protein, a complement activating animal lectin.

Mannan-binding protein is an animal serum lectin (i.e. a molecule with the ability to bind specifically to certain carbohydrate structures). The relevant carbohydrate ligands are found on many pathogenic microorganisms. After binding to suitable carbohydrate ligands, mannan-binding protein is found to be an activator of the classical pathway of complement via an activation of the C1r2C1s2 complex, i.e. antibody and C1q independent. The molecular organization of MBP resembles that of C1q with a distinct division of collagen-like and globular amino acid sequences. This molecular similarity seems to be the basis for the common functional activity of the two proteins. MBP may play an important protective role, especially at early stages of infection prior to the generation of the specific humoral and cellular defence system. The paper explores the structure and the physiological functions of mannan-binding protein.

Animals↗