Complement C4b

Normally, when the complement classical pathway was activated by the immune complex or the lectin pathway was activated by glycoprotein components on pathogen membrane surfaces, the proteases C1s and MASP-2 were activated, respectively. C1s and MASP-2 cleave the complement component 4 (C4) alpha chain into C4a and C4b fragments. C4a serves as an anaphylatoxin involved in local inflammation. C4b is an important member of the complement cascade that participates in the formation of the C3 convertases (C4bC2b) and C5 convertases (C4bC2bC3b).

Human C4b is a glycosylated polypeptide with 188 kDa, containing 12 domains (eight macroglobulin domains, a thioester domain, a CUB domain, fibronectin type III domain, and a C345C C-terminal domain). The cleavage of C4 into C4b is realized by the removal of the ANA domain, also named as C4a fragment. The activated C4b can covalently attach to hydroxyl or amine groups on pathogenic or target surfaces, forming the C3/C5 convertase enzyme complex. Surface-bound C4b has binding sites for the CCP module containing complement regulatory proteins, including C4b binding protein (C4BP), complement receptor 1, membrane cofactor protein, decay accelerator factor, and factor I. When binds to the complement regulatory proteins, C4b will be cleaved into C4c and C4d, resulting in loss of complement activation activity. The abnormality of C4b is related to complement dysfunction, immunodeficiency, and systemic lupus erythematosus.

Fig.1 The structural changes accompanying activation of C4 and its transition to C4b. (Mortensen, 2015)

Reference

1. Mortensen, S.; et al. Structural Basis for the Function of Complement Component C4 within the Classical and Lectin Pathways of Complement. The Journal of Immunology. 2015, 194(11): 5488-5496.