Complement Component C1

Introduction to Complement Component C1

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.

Structure of C1

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.

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Introduction to Complement Component C1 Mechanism of C1 Activation C1-related assay protocols by target Complement C1 in Autoimmune Diseases Complement C1 in Neurodegenerative Diseases Complement C1 in Infectious Diseases Complement C1 in Cancer Targeting C1 in Disease
C1q: Recognizes and binds to immune complexes (antibody-antigen complexes). C1r and C1s: Serine proteases involved in the cleavage of downstream components like C4

Functions of C1q

Large, hexameric structure with a central stalk and six globular heads

  • Binds to Fc regions of IgG or IgM antibodies
  • Binds to pathogen surfaces directly or to apoptotic cells

Functions of C1r

A serine protease

  • Becomes activated when C1q binds to its target
  • Activation of C1r leads to the cleavage and activation of C1s

Functions of C1s

A serine proteases

  • Once activated by C1r, C1s cleaves C4 and C2 to form C4b2a, the C3 convertase, which drives further complement activation.

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Mechanism of 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:

01C1 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.

02C1 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.

03Spontaneous 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-related Assay Protocols by Target

Complement C1 in Autoimmune Diseases

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).

Systemic Lupus Erythematosus (SLE)

  • Role of complement C1 in immune complex clearance of SLE
  • Genetic polymorphisms of complement C1 of SLE
  • C1 inhibitor function in SLE
  • C1q as a biomarker for SLE
  • Therapeutic targeting of C1 complement pathway
  • C1 complex and T cell dysregulation in SLE
  • Influence of C1 on B cell function in SLE
Systemic lupus erythematosus (Creative Biolabs Authorized)
Systemic lupus erythematosus (Creative Biolabs Authorized)

Rheumatoid Arthritis (RA)

  • Interaction between complement C1 and cytokines in RA
  • Modulation of complement C1 in RA animal models
  • Effect of C1 inhibitors in RA models

Complement C1 in Neurodegenerative Diseases

Beyond autoimmune conditions, C1 is implicated in neurodegenerative diseases, where it contributes to both protective and pathological processes in the central nervous system (CNS).

Alzheimer’s Disease (AD)

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:

1 Role of complement C1 in amyloid-beta clearance
2 Complement C1 and synaptic function
3 C1q and microglial activation in AD
4 Complement C1 and calcium signaling in neurons

Multiple Sclerosis (MS)

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:

1 Role of complement C1 in neuroinflammation
2 Complement C1 and blood-brain barrier dysfunction
3 Complement C1’s role in oligodendrocyte survival and myelin repair
4 C1q and its role in apoptosis and phagocytosis in MS

Complement C1 in Infectious Diseases

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.

Bacterial Infections

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:

  • Streptococcus pneumoniae
  • Neisseria meningitidis
  • Escherichia coli
  • Haemophilus influenzae

Viral Infections

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:

  • Influenza virus
  • HIV
  • Hepatitis B and C viruses
  • SARS-CoV-2

Complement C1 in Cancer

Complement Mechanism Specific Description
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.

Targeting C1 in Disease

Given its central role in disease processes, targeting C1 and the classical pathway has emerged as a potential therapeutic strategy for various diseases.

Our Services

Creative Biolabs is dedicated to offering a full range of biotherapeutics development services. Based on our well-established antibody engineering platform, protease inhibitor platform, and drug discovery platform, we are fully equipped to reach out our hands to our clients who are doing or may have the desire to work on complement C1 for drug discovery and validation.

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.

Reference

  1. Hamers, Sebastiaan MWR, et al. "Selection and characterization of a peptide-based complement modulator targeting C1 of the innate immune system." RSC chemical biology 5.8 (2024): 787-799, used under [CC BY 3.0](https://creativecommons.org/licenses/by/3.0/).
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