C4b binding protein (C4BP) is a 540 kDa plasma glycoprotein synthesized in the liver, presenting in circulation at a concentration of ~200 mg/L. Human C4BP is a protein complex composed of six/seven identical α chains and a β single chain, named as C4BPA and C4BPB, respectively. Both α chain and β chain contain two cysteine residues and an amphipathic α-helix, which are attached by disulfide bonds forming a unique spider-like structure. Each α chain contains eight complement control protein (CCP) repeat domains and a binding site for the activated complement C4b, whereas, the β chain contains three CCP domains and a protein S binding site.
In the complement system, C4BP functions as a soluble inhibitor of the complement classical pathway and complement lectin pathway. Firstly, C4BP serves as a cofactor to the complement factor I (a regulatory enzyme inhibiting complement activation), in which the complement C4b bind to the α chains of the C4BP (CCP1-3 domains) and is immediately inactivated. Secondly, C4BP accelerates the decay of the unstable C3 convertase (C4bC2a), and binds to complement C3b preventing the assembly of the C5 convertase. Thirdly, C4BP also interacts with other ligands, such as vitamin K-dependent anticoagulant protein S (via the β chain), heparin, C-reactive protein, and some bacterial proteins. It has been reported that C4BP deficiency or mutation was involved in atypical hemolytic uremic syndrome (aHUS) and recurrent pregnancy loss.
Fig. 1 Structure of C4BP.1
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Reference
Breda, Leandro CD, et al. "Fine mapping of the interaction between C4b-binding protein and outer membrane proteins LigA and LigB of pathogenic Leptospira interrogans." PLoS neglected tropical diseases 9.10 (2015): e0004192.
Fig. 1 Structure of C4BP.1