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.
Large, hexameric structure with a central stalk and six globular heads
A serine protease
A serine proteases
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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:
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.
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.
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.
Dysregulation of C1 can lead to inappropriate complement activation or failure to clear immune complexes, contributing to the development of autoimmune diseases. The most prominent examples are systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).
Beyond autoimmune conditions, C1 is implicated in neurodegenerative diseases, where it contributes to both protective and pathological processes in the central nervous system (CNS).
C1q binds to Aβ plaques and initiates the complement cascade, resulting in the activation of microglia (the brain's immune cells) and the release of pro-inflammatory cytokines. This chronic activation of complement can lead to neuroinflammation and neuronal damage, exacerbating disease progression. We offer the following research solutions, including but not limited to:
Complement activation, particularly via the classical pathway, is thought to contribute to demyelination and axonal damage in MS. C1q has been found in MS lesions, and its presence correlates with areas of myelin loss and inflammation. We offer the following research solutions, including but not limited to:
The classical pathway, and C1 in particular, plays a crucial role in fighting infections by recognizing and neutralizing pathogens. However, certain pathogens can hijack or evade this system, leading to enhanced disease progression.
C1q binds to bacterial surface antigens, triggering complement activation and promoting opsonization, which enhances phagocytosis by macrophages and neutrophils. Some bacteria, such as Staphylococcus aureus, have evolved mechanisms to evade complement attack by producing proteins that inhibit C1q binding or interfere with the classical pathway. Several bacterial infections are commonly studied:
C1q can bind to viral particles and neutralize them by activating the complement cascade. In some viral infections, such as HIV and HSV, complement activation can either enhance viral clearance or contribute to tissue damage. Certain viruses also encode proteins that interfere with C1 function, allowing them to evade immune surveillance. Several viral infections are commonly studied:
Complement Mechanism | Specific Description |
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Tumor Immune Surveillance | C1q and the classical pathway can promote the recognition and destruction of tumor cells. C1q can bind to tumor antigens and initiate complement activation, leading to the opsonization and phagocytosis of tumor cells by macrophages and other immune cells. |
Pro-tumor Effects | Chronic inflammation driven by complement activation can promote tumor growth and metastasis. C1q-mediated complement activation in the tumor microenvironment can enhance angiogenesis, suppress anti-tumor immune responses, and promote tissue remodeling. |
Given its central role in disease processes, targeting C1 and the classical pathway has emerged as a potential therapeutic strategy for various diseases.
Complement component C1 is a pivotal player in the immune system, facilitating the clearance of pathogens, immune complexes, and apoptotic cells through the classical pathway of complement activation. However, dysregulation of C1 is associated with a wide range of diseases, including autoimmune disorders, neurodegenerative conditions, infectious diseases, and cancer. Understanding the dual roles of C1 has opened new avenues for therapeutic interventions. Targeting C1 and its associated pathways offers promising strategies for treating diseases where complement dysregulation plays a central role.
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