C4b binding protein binds Protein S C3 convertases spontaneously dissociate Factor H binds to C3b Factor H binds host cell surface markers Factor I inactivates MCP/CR1-bound C4b/C3b Complement factor I binds to MCP, CR1:C4b, C3b DAF accelerates C3bBb/C4bC2a dissociation DAF binds C3bBb, C4bC2a Complement factor I binds C4BP C4b-binding protein binds C4b C4b binding protein binds C4bC2a Complement factor I inactivates C4BP-bound C4b MCP binds C3b, C4b C4b binding protein displaces C2a Complement factor I complex formation Factor H displaces Bb Factor H binds to C3bBb Factor H binds to membrane-associated C3b Factor I inactivates Factor H-boundC3b Complement factor I binds to membrane-associated Factor H:C3b Factor I inactivates plasma Factor H-bound C3b Complement factor I binds to extracellular Factor H:C3b CR1 binds C3bBb/C4bC2a Displacement of C2a/Bb by CR1 PathwayStep6855 PathwayStep6854 PathwayStep6857 PathwayStep6856 PathwayStep6859 PathwayStep6858 PathwayStep6860 PathwayStep6861 PathwayStep6862 PathwayStep6846 PathwayStep6845 PathwayStep6844 PathwayStep6843 PathwayStep6849 PathwayStep6848 PathwayStep6847 PathwayStep6852 PathwayStep6853 PathwayStep6850 PathwayStep6851 PathwayStep6842 PathwayStep6841 PathwayStep6840 PathwayStep6839 Regulation of Complement cascade Authored: Jupe, S, 2010-10-26 Edited: Jupe, S, 2010-11-01 GENE ONTOLOGYGO:0030449 Pubmed15476920 Pubmed16011850 Pubmed18197169 Pubmed19730437 Pubmed20720586 Pubmed21979047 Reactome Database ID Release 43977606 Reactome, http://www.reactome.org ReactomeREACT_118707 Reviewed: Bradley, DT, 2012-02-13 Reviewed: Fraczek, LA, 2012-02-13 Two inherent features of complement activation make its regulation very important: <br>1. There is an inherent positive feedback loop because the product of C3 activation forms part of an enzyme that causes more C3 activation.<br>2. There is continuous low-level activation of the alternative pathway (see Spontaneous hydrolysis of C3 thioester).<br><br>Complement cascade activation is regulated by a family of related proteins termed the regulators of complement activation (RCA). These are expressed on healthy host cells. Most pathogens do not express RCA proteins on their surface, but many have have found ways to evade the complement system by stably binding the RCA that circulates in human plasma (Lambris et al. 2008); trapping RCA is by far the most widely employed strategy for avoiding the complement response. RCA recruitment is common in bacteria such as E. coli and streptococci (Kraiczy & Würzner 2006) and has also been described for viruses, fungi and parasites. RCA deposition and the complement system also have an important role in tissue homeostasis, clearing dead cells and debris, and preventing damage from oxidative stress (Weismann et al. 2011).<br><br>RCA proteins control complement activation in two different ways; by promoting the irreversible dissociation (decay acceleration) of complement convertases and by acting as cofactors for Complement factor I (CFI)-mediated cleavage of C3b and C4b.<br>Decay accelerating factor (DAF, CD55), Complement factor H (FH), Membrane Cofactor Protein (MCP) and Complement receptor 1 (CR1) are composed of arrays of tandem globular domains termed CCPs (complement control protein repeats) or SCRs (short consensus repeats). CR1, MCP and FH are cofactors for the CFI-mediated cleavage of C3b, generating iC3b. CR1 and MCP are also cofactors for C4b cleavage.<br>C4BP is an additional cofactor for the CFI-mediated cleavage of C4b.