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 systems for drug discovery and validation.
The complement system is composed of approximately 30 fluid-phase and cell-membrane proteins and can be activated essentially by three pathways which are the classical, mannose-binding lectin, and alternative pathways. As part of the immune system, the complement component 1q (C1q) is protein complex that is involved in the complement cascade. C1q forms a C1 complex with C1r and C1s. Produced by the plasma cells, antibodies bind antigens and form the antigen-antibody complex. The C1 complex becomes activated once C1q binds to the antigen-antibody complex. The classical complement pathway of the complement system is initiated by the activation of the C1 complex.
Fig.1 The 3D model of human C1q. (Pflieger, 2010)
Function
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Complement function
In the complement system, C1q functions in the classical pathway. It plays an important role in the recognition of antigen-antibody complexes and the initiation of the cascade. The molecular weight of the human C1q molecule is approximately 460 kD, and it consists of 18 polypeptide chains (6A, 6B, and 6C). The A chain (223 residues), B chain (226 residues), and C chain (217 residues) each have a short (3-9 residues) N-terminal region (containing a half-cysteine residue involved in inter-chain disulfide bond formation).
The first component of complement C1 is a complex of three glycoproteins, which are C1q, C1r, and C1s. C1r and C1s form a Cazf-dependent tetrameric proenzyme complex, C1r-C1s-C1r-C1s, which interacts with the Clq collagen domain. Binding of Clq to immune complexes (IgG or IgM) via the gC1q domain, induces a conformational change in the collagen region of C1q, which leads to the auto-activation of C1r. Activated C1r, in turn, activates C1s. The activated C1 complex then cleaves components C4 and C2 in the classical pathway of the complement system, forming the C3 convertase for cleaving C3.
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Modulation of Dendritic Cells Maturation and Functions by C1q
Dendritic cells (DCs) are antigen capturing and presenting cells of innate immunity in mammalian cells. Interstitial/dermal DCs (IDDCs) produce C1q, following stimulation with IL-4 and granulocyte macrophage-colony stimulating factor (GM-CSF). C1q has been shown to be produced by renal DCs in a mouse model of progressive lupus nephritis. Renal sections of mice showed significantly higher expression of C1q in tubule-interstitium of old MRL/lpr mice than young MRL/lpr mice.
C1q binds to monocyte-derived immature DCs. This causes the NF-kappa B nuclear translocation from the cytoplasm. C1q enhances maturation of DC exhibiting a higher level of surface expression of CD83, CD86, HLA-DR, and CCR7. Both gC1q and collagen region can induce DC maturation. Leukocyte-associated Ig-like receptor (LAIR) is a transmembrane protein belonging to the immunoglobulin superfamily. It is expressed on NK cells, B cells, monocytes, human fetal thymocytes, and T cells. Binding to LAIR by C1q elicits the activation of LAIR-1 signaling. C1q inhibits the GM-CSF and IL-4 stimulated differentiation of monocytes into DCs. Interaction of C1q with LAIR-2 reduces the expression of LAIR-1 and CD14, suggesting that the C1q-mediated differentiation of DCs is reversed by LAIR-2.
C1q Related Disease
C1q is a normal protein floating in the circulation of healthy people. C1q deficiency renders hosts more susceptible to microbial infections. Also, C1q deficiency is linked to skin lesions, Glomerulonephritis and systemic lupus erythematosus (SLE)-like syndrome. The consistent association of C1q deficiency with SLE-like disorders is not directly explained by its classical role in complement activation. The ability of the complement system to enhance apoptotic cell (AC) phagocytosis or clearance is also relevant.
With professional knowledge and rich research experiences in drug discovery and complement therapeutic field, Creative Biolabs' outstanding research groups are confident in providing high-quality biotherapeutics development services based on the complement C1q of the complement system. We offer turn-key or ala carte services customized to our client’s needs. If you are interested in our platform or you are calling for our services, please contact us for detailed information.
Reference
1. Pflieger, D.; et al. Analysis of human C1q by combined bottom-up and top-down mass spectrometry: detailed mapping of post-translational modifications and insights into the C1r/C1s binding sites. Mol Cell Proteomics. 2010, 9(4), 593-610.
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Questions & Answer
A: Yes, there are several therapeutic strategies being explored to target C1q. These include the development of monoclonal antibodies that specifically bind to C1q, aiming to modulate its activity or enhance immune complex clearance. Additionally, small molecules or peptides that mimic the binding sites of C1q could be potential therapeutic agents.
A: Targeting C1q as a therapeutic strategy for neurodegenerative diseases is being explored. Inhibiting C1q binding to abnormal protein aggregates or blocking downstream complement activation could potentially reduce neuroinflammation and neuronal damage in these diseases.
A: Yes, there are natural inhibitors of C1q that regulate its activity. For example, C1q-binding proteins, such as C1q receptor (C1qR) and C1q inhibitory protein (C1qIP), can bind to C1q and modulate its function. These natural inhibitors play a role in maintaining complement homeostasis and preventing excessive complement activation.
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