Interaction of C1-inhibitor with the C1r and C1s subcomponents in human C1

doi:10.1016/0005-2795(79)90494-X

Biochimica et Biophysica Acta (BBA) - Protein Structure

Volume 576, Issue 1, 25 January 1979, Pages 151-162

https://doi.org/10.1016/0005-2795(79)90494-X Get rights and content

Abstract

1.
1.|Insoluble IgG-ovalbumin aggregates were used to bind and activate Cl from human serum. The bound C $1$ provided a useful reagent for studying the interaction of C $1$ subcomponents with C $1$ -inhibitor.
2.
2.|C $1$ -inhibitor bound to both subcomponents (C $1$ r and C $1$ s in C $1$ and formed stable complexes of respective apparent molecular weights 197 000 and 185 000, as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The binding reaction proceeded more readily with C $1$ s than with C $1$ r and was correlated with the inhibition of C $1$ s esterase activity.
3.
3.|At physiological ionic strength, binding of C $1$ -inhibitor to subcomponents C $1$ r and C $1$ s caused release of these subcomponents from the C $1$ -immune aggregates complex, indicating that C $1$ -inhibitor binding decreased the inter-subcomponent binding forces in C $1$ . At low ionic strength, however, this relase did not occur.

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Pf92is a member of the parasite 6-cys protein family and acts by recruiting FH to the merozoite surface (Kennedy et al., 2016), mimicking host cells by dissociating C3 convertase and allowing the inactivation of C3b by FI (Loos, 1985; Whaley and Ruddy, 1976). Likewise, PfMSP3.1 block complement activation by recruiting C1-INH (Kennedy et al., 2017) inhibiting the formation of CP and LP initiator complexes (Arlaud et al., 1979; Matsushita et al., 2000). P. falciparum complement inhibition mechanisms are summarized in Fig. 3.
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SERPING1 is a relative of the above presented inhibitors of coagulation and it is known as the only C1 inhibitor (and therefore sometimes abbreviated as C1INH). It controls the activity of C1r and C1s by preventing their auto-activation or by enforcing their dissociation from C1 complex [97]. Moreover, SERPING1 inhibits the activity of plasma-thromboplastin antecedent and Hageman factor (coagulation factors XI and XII) [98] as well as the mannan-binding lectin-associated serine proteases (MASPs) [99].
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This suggests two potential activation mechanisms: either C1q binding to the correct pattern allows allosteric activation of C1r and C1s in the complex, and their activities are in turn controlled by C1INH; or the C1 complex under physiological conditions comprises also reversibly associated C1INH, which is forced out of the complex upon binding to the correct pattern, allowing activation of C1r and C1s to occur. Additionally, it has been found that upon inhibition of C1r and C1s by C1INH, these dissociate from C1q [42–44]. Regardless of the activation mechanism, the importance of C1INH in regulating the physiological complex is obvious.
MASP-1 is a protease of the lectin pathway of complement. It is homologous with MASP-2, previously thought both necessary and sufficient for lectin pathway activation. Recently MASP-1 has taken centre stage with the observation that it is crucial to the activation of MASP-2 and thus central to complement activation. Numerous additional functions have been suggested for MASP-1 and its importance is obvious. Yet, thorough analyses of proteolytic activities and physiological roles in the human scenario have been hampered by difficulties in purifying or producing full-length human MASP-1. We present the successful expression of full-length recombinant human MASP-1 entirely in the zymogen form in a mammalian expression system. We found that the catalytic activity of MASP-1 suppresses its expression through rapid auto-activation and auto-degradation. This auto-degradation was not inhibited by the addition of inhibitors to the culture medium, and it was subsequently found to occur intracellularly. Numerous mutations aimed at attenuating auto-activation or preventing auto-degradation failed to rescue expression, as did also attempts at stabilizing the protease by co-expression with MBL or ficolins or expression in hepatocyte cell lines, representing the natural site of synthesis. The active protease was finally produced through co-expression with the serine protease inhibitor C1 inhibitor. We demonstrate that the expressed protease is capable of binding MBL and auto-activating, and is catalytically active. We have generalized the concept to the expression also of MASP-2 entirely in its zymogen form and with improved yields. We suggest a general advantage of expressing aggressive, autocatalytic proteases with their cognate inhibitors.
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Dinu et al. 2007) reported a C7 haplotype was associated with reduced risk of developing wet AMD in patients with at least one CFH gene Y402H risk allele (see below). C1 inhibitor, otherwise known as SERPING1 (serpin peptidase inhibitor, clade G, member 1) (Silverman et al. 2001) forms stable complexes with C1 subunits C1r and C1s (Ziccardi and Cooper 1976; Arlaud et al. 1979), and as a result irreversibly inhibits the classical complement pathway. SERPING1 also inhibits the lectin pathway (Kerr et al. 2008), and has a range of non-specific anti-inflammatory activities (Davis et al. 2007).
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Interaction of C1-inhibitor with the C1r and C1s subcomponents in human C1

Abstract

FEBS Lett.

Biochim. Biophys. Acta

Methods Enzymol.

J. Biol. Chem.

Eur. J. Biochem.

J. Clin. Invest.

Nature

Biochem. J.

Biochemistry

Interaction of C $1$ -inhibitor with the C $1$ r and C $1$ s subcomponents in human C $1$