Complement system is a group of serum proteins used to fight infections and plays an important role in the immune defense system. When the complement system is activated, it will trigger a series of ordered biochemical reactions, accompanied by the production of a variety of inflammatory mediators, and ultimately achieve the purpose of eliminating and removing invading microorganisms. Complement component 1 (C1) is a key protein that initiates the classical activation pathway of the complement system. After activated, it will continue to activate the second (C2) and fourth (C4) complement components, triggering the complement cascade.
Under physiological conditions, C1 contains two weakly interacting subunits C1q and C1r2s2, where C1q contains the binding site of activator and protein, and C1r2s2 has enzymatic potential. From the current molecular principles related to the activation of C1 and its physiological control, C1 has attracted much attention not only because of its importance as the originator of the classical complement pathway, but also because it is the most easily defined and studied immunoglobulin functional mediator. In addition, C1 itself has a biochemical model worthy of repeated study, involving specific protein-protein interactions, induced conformational changes, and limited proteolytic activation.
Fig. 1 Complement pathway.1
C1 Activation
C1 generally exists in a precursor state and becomes active only after being activated. The most apparent physicochemical change in C1 upon activation is the cleavage of each 85000 dalton C1r and C1s polypeptide polypeptide chain into two disulfide held chains of approximately 57000 and 28000 daltons. This limited proteolysis will confer C1r and C1s serine protease activity. The natural substrate of activated C1r is C1s, while activated C1s cleaves C2 and C4. C1r and C1s are highly specific proteases whose enzyme activity is regulated by interactions with C1q and their substrates C2 and C4. C1r and C1s also cleave various synthetic substrates, of which thioester peptides are particularly good substrates. C1 activation can be roughly divided into three ways：
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C1 Activation Induced by Immune Complexes. Certain antigen-antibody complex interactions activate C1. In humans, IgG and IgM bind C1, but IgA, IgD, and IgE do not. The C1 binding site has been assigned to the Cγ2 domain of the Fc portion of IgG and Cμ4 region of the IgM Fc. However, complement related synthetic peptides similar to "C1q binding sites" and inhibiting C1q-IgG interactions do not originate from this region of IgG. This suggests that this peptide inhibition phenomenon may be non-specific.
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C1 Activation Induced by Nonimmune Substances. In addition to being activated by antibodies, C1 can also be activated by non-immune substances including viruses, bacteria, carbohydrates, C-reactive proteins, myelin membranes, and endotoxins. Although this antibody-independent complement activation pathway is beneficial to the host when the immune system responds to foreign invasion, it also involves some pathogenic mechanisms.
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Spontaneous C1 Activation. Studies have shown that C1 can be spontaneously activated through an intramolecular autocatalytic mechanism. This fact makes it easier than ever to study the mechanism of C1 activation at the molecular level through biophysical techniques that are easier to apply without complex activators. In addition, a key comparison of spontaneous and activator-induced C1 activation will reveal the role of activators in the intrinsic C1 activation process.
C1 Protein Function Unrelated to Complement System
In addition to the initiation of the classical complement pathway, the C1 protein may have other physiological functions. For example, human peripheral blood leukocytes have a receptor for C1q. Significantly the collagen-like portion of C1q, which binds to the receptors, is inaccessible in macromolecular C1. But after C1 is broken down, C1q bound to the immune complex can freely react with the C1q receptor, potentially acting as a bridge between the immune complex and effector cells. Therefore, C1q may play a direct role in the destruction and clearance of classical pathway activators. This hypothesis is supported by reports on C1q-dependent mechanisms of cytotoxicity.
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