Complement system is an essential defense line in our immune responses. As an advanced leader in the pharmaceutical field, Creative Biolabs is dedicated to providing the largest portfolio of complement products and standard or custom complement services. Aided by our versatile drug discovery platform, we can offer high-quality products and valuable suggestions to promote your specific projects. Based on the complement system, we have successfully developed a series of innovative and effective complement regulators (including C4b-binding protein) to promote or block the complement activation.
Introduction of C4BP
C4b-binding protein (C4BP) is the main fluid-phase inhibitor of complement cascade. Possessing decay-accelerating activity, C4BP acts as a regulatory protein mainly involved in the classical and the lectin pathways. C4BP is a large glycoprotein (500 kDa) with a plasma concentration 200 μg/ml. It is mainly synthesized in the liver. It serves as a functional cofactor in factor I-mediated cleavage of C4b and C3b and accelerates decay of C3-convertase. Now, it has become an important target for therapy exploration to regulate the complement activation.
Structure of C4BP
C4BP is a multimeric protein circulating in human plasma in three isoforms based on different combinations of α (70 kDa) and β (45 kDa) chains. The predominant isoform (α7β1) has an oligomeric structure and consists of seven α chains (70 kDa), encoded by C4BPA, and a single β chain (45 kDa), encoded by C4BPB covalently linked by disulfide bonds at the C terminus. The α-chain confers C4BP complement inhibitory activity, while β-chain binds anticoagulant protein S and docks the molecule to negatively charged phospholipids exposed, e.g., on the surface of dying cells. Both α- and β- chains are composed predominantly of tandemly arranged short consensus repeats (SCR) of approximately 60 amino acids in length.
Fig.1 Structure of C4BP. (Rezende, 2004)
Functions of C4BP
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The main role of C4BP is to function as an essential cofactor for complement factor I (CFI), allowing it to bind and thereby mediating the proteolytic cleavage of C4b and, to a lesser extent, of C3b. It also acts as the regulator of C3 convertase of the classical pathway (CP) and the lectin pathway (LP), accelerating decay of C3-convertase, thus inhibiting the activation of CP and LP.
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C4BP interacts not only with C4b but also with vitamin K-dependent anticoagulant protein S (PS), heparin, serum amyloid P component (SAP), indicating the unequivocal link between the complement and blood coagulation systems.
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C4BP can be recruited onto the apoptotic or necrotic cells as well as DNA, helping clearance after injury. This process is mediated by the Gla domain of protein S and does not affect the ability of C4BP to inhibit complement. Furthermore, C4BP frequently binds to the surface of various pathogens, which allows these to evade the immune response.
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C4BP prevents complement-mediated inflammation both in solution and on self-molecules recognized by C1q, such as amyloid.
Fig.2 C4BP interaction with GAS M protein. (Lindahl, 2016)
C4BP Deficiency
Primary deficiency of C4BP was present in a patient with disease clinically resembling Behçet's disease, characterized by genital and oral ulceration, cutaneous vasculitis and synovitis.
Because of the importance in the regulation of complement activation, C4BP has become a promising target for therapy exploration and clinical trial. Creative Biolabs combines our advanced technologies with long-term scientific expertise to offer a full range of formulation development services for complement products. Please contact us for more information.
References
1. Rezende, S.M.; et al. Coagulation, inflammation, and apoptosis: different roles for protein S and the protein S-C4b binding protein complex. Blood. 2004, 103(4): 1192-1201.
2. Lindahl, G.; Persson, J.J. Structural biology: Variability without change. Nature microbiology. 2016, 1(11): 16218.
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