Complement cascade (Homo sapiens)

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Description

In the complement cascade, a panel of soluble molecules rapidly and effectively senses a danger or damage and triggers reactions to provide a response that discriminates among foreign intruders, cellular debris, healthy and altered host cells (Ricklin D et al. 2010). Complement proteins circulate in the blood stream in functionally inactive states. When triggered the complement cascade generates enzymatically active molecules (such as C3/C5 convertases) and biological effectors: opsonins (C3b, C3d and C4b), anaphylatoxins (C3a and C5a), and C5b, which initiates assembly of the lytic membrane attack complex (MAC). Three branches lead to complement activation: the classical, lectin and alternative pathways (Kang YH et al. 2009; Ricklin D et al. 2010). The classical pathway is initiated by C1 complex binding to immune complexes, pentraxins or other targets such as apoptotic cells leading to cleavage of C4 and C2 components and formation of the classical C3 convertase, C4bC2a. The lectin pathway is activated by binding of mannan-binding lectin (MBL) to repetitive carbohydrate residues, or by binding of ficolins to carbohydrate or acetylated groups on target surfaces. MBL and ficolins interact with MBL-associated serine proteases (MASP) leading to cleavage of C4 and C2 and formation of the classical C3 convertase, C4bC2a. The alternative pathway is spontaneously activated by the hydrolysis of the internal thioester group of C3 to give C3(H2O). Alternative pathway activation involves interaction of C3(H2O) and/or previously generated C3b with factor B, which is cleaved by factor D to generate the alternative C3 convertases C3(H2O)Bb and/or C3bBb. All three pathways merge at the proteolytic cleavage of component C3 by C3 convertases to form opsonin C3b and anaphylatoxin C3a. C3b covalently binds to glycoproteins scattered across the target cell surface. This is followed by an amplification reaction that generates additional C3 convertases and deposits more C3b at the local site. C3b can also bind to C3 convertases switching them to C5 convertases, which mediate C5 cleavage leading to MAC formation. Thus, the activation of the complement system leads to several important outcomes:

opsonization of target cells to enhance phagocytosis,
lysis of target cells via membrane attack complex (MAC) assembly on the cell surface,
production of anaphylatoxins C3a/C5a involved in the host inflammatory response,
C5a-mediated leukocyte chemotaxis,
and clearance of antibody-antigen complexes.

The complement system is able to distinguish between pathological and physiological challenges, i.e. the outcomes of complement activation are predetermined by the trigger and are tightly tuned by a combination of initiation events with several regulatory mechanisms. These regulatory mechanisms use soluble (e.g., C4BP, CFI and CFH) and membrane-bound regulators (e.g., CR1, CD46(MCP), CD55(DAF) and CD59) and are coordinated by complement receptors such as CR1, CR2, etc.

In response to microbial infection complement activation results in flagging microorganisms with opsonins for facilitated phagocytosis, formation of MAC on cells such as Gram-negative bacteria leading to cell lysis, and release of C3a and C5a to stimulate downstream immune responses and to attract leukocytes. Most pathogens can be eliminated by these complement-mediated host responses, though some pathogenic microorganisms have developed ways of avoiding complement recognition or blocking host complement attack resulting in greater virulence (Lambris JD et al. 2008; Serruto D et al. 2010).All three complement pathways (classical, lectin and alternative) have been implicated in clearance of dying cells (Mevorach D et al. 1998; Ogden CA et al. 2001; Gullstrand B et al.2009; Kemper C et al. 2008). Altered surfaces of apoptotic cells are recognized by complement proteins leading to opsonization and subsequent phagocytosis. In contrast to pathogens, apoptotic cells are believed to induce only a limited complement activation by allowing opsonization of altered surfaces but restricting the terminal pathway of MAC formation (Gershov D et al. 2000; Braunschweig A and Jozsi M 2011). Thus, opsonization facilitates clearance of dying cells and cell debris without triggering danger signals and further inflammatory responses (Fraser DA et al. 2007, 2009; Benoit ME et al. 2012). C1q-mediated complement activation by apoptotic cells has been shown in a variety of human cells: keratinocytes, human umbilical vein endothelial cells (HUVEC), Jurkat T lymphoblastoid cells, lung adenocarcinoma cells (Korb LC and Ahearn JM 1997; Mold C and Morris CA 2001; Navratil JS et al. 2001; Nauta AJ et al. 2004). In addition to C1q the opsonization of apoptotic Jurkat T cells with MBL also facilitated clearance of these cells by both dendritic cells (DC) and macrophages (Nauta AJ et al. 2004). Also C3b, iC3b and C4b deposition on apoptotic cells as a consequence of activation of the complement cascade may promote complement-mediated phagocytosis. C1q, MBL and cleavage fragments of C3/C4 can bind to several receptors expressed on macrophages (e.g. cC1qR (calreticulin), CR1, CR3, CR4) suggesting a potential clearance mechanism through this interaction (Mevorach D et al. 1998; Ogden CA et al. 2001). Apoptosis is also associated with an altered expression of complement regulators on the surface of apoptotic cells. CD46 (MCP) bound to the plasma membrane of a healthy cell protects it from complement-mediated attack by preventing deposition of C3b and C4b, and reduced expression of CD46 on dying cells may lead to enhanced opsonization (Elward K et al. 2005). Upregulation of CD55 (DAF) and CD59 on apoptotic cell surfaces may protect damaged cells against complement mediated lysis (Pedersen ED et al. 2007; Iborra A et al. 2003; Hensel F et al. 2001). In addition, fluid-phase complement regulators such as C4BP, CFH may also inhibit lysis of apoptotic cells by limiting complement activation (Trouw LA et al 2007; Braunschweig A and Jozsi M. 2011).Complement facilitates the clearance of immune complexes (IC) from the circulation (Chevalier J and Kazatchkine MD 1989; Nielsen CH et al. 1997). Erythrocytes bear clusters of complement receptor 1 (CR1 or CD35), which serves as an immune adherence receptor for C3 and/or C4 fragments deposited on IC that are shuttled to liver and spleen, where IC are transferred and processed by tissue macrophages through an Fc receptor-mediated process.Complement proteins are always present in the blood and a small percentage spontaneously activate. Inappropriate activation leads to host cell damage, so on healthy human cells any complement activation or amplification is strictly regulated by surface-bound regulators that accelerate decay of the convertases (CR1, CD55), act as a cofactor for the factor I (CFI)-mediated degradation of C3b and C4b (CR1, CD46), or prevent the formation of MAC (CD59). Soluble regulators such as C4BP, CFH and FHL1 recognize self surface pattern-like glycosaminoglycans and further impair activation.Complement components interact with other biological systems. Upon microbial infection complement acts in cooperation with Toll-like receptors (TLRs) to amplify innate host defense. Anaphylatoxin C5a binds C5a receptor (C5aR) resulting in a synergistic enhancement of the TLR and C5aR-mediated proinflammatory cytokine response to infection. This interplay is negatively modulated by co-ligation of TLR and the second C5a receptor, C5L2, suggesting the existence of complex immunomodulatory interactions (Kohl J 2006; Hajishengallis G and Lambris JD 2010). In addition to C5aR and C5L2, complement receptor 3 (CR3) facilitates TLR2 or TLR4 signaling pathways by promoting a recruitment of their sorting adaptor TIRAP (MAL) to the receptor complex (van Bruggen R et al. 2007; Kagan JC and Medzhitov R 2006). Complement may activate platelets or facilitate biochemical and morphological changes in the endothelium potentiating coagulation and contributing to homeostasis in response to injury (Oikonomopoulou K et al. 2012). The interplay of complement and coagulation also involves cleavage of C3 and C5 convertases by coagulation proteases, generating biologically active anaphylatoxins (Amara U et al. 2010). Complement is believed to link the innate response to both humoral and cell-mediated immunity (Toapanta FR and Ross TM 2006; Mongini PK et al. 1997). The majority of published data is based on experiments using mouse as a model organism. Further characterization of the influence of complement on B or T cell activation is required for the human system, since differences between murine models and the human system are not yet fully determined. Complement is also involved in regulation of mobilization and homing of hematopoietic stem/progenitor cells (HSPCs) from bone marrow to the circulation and peripheral tissue in order to accommodate blood cell replenishment (Reca R et al. 2006).Thus, the complement system orchestrates the host defense by sensing a danger signal and transmitting it into specific cellular responses while extensively communicating with associated biological pathways ranging from immunity and inflammation to homeostasis and development.

N.B. Originally the larger fragment of Complement Factor 2 (C2) was designated C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. Recent literature may use the updated nomenclature and refer to the larger C2 fragment as C2b, and refer to the classical C3 convertase as C4bC2b. Throughout this pathway Reactome adheres to the original convention to agree with the current (Sep 2013) Uniprot names for C2 fragments. View original pathway at:Reactome.</div>

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Degen SJ, Davie EW.; ''Nucleotide sequence of the gene for human prothrombin.''; PubMed Europe PMC Scholia
Forneris F, Ricklin D, Wu J, Tzekou A, Wallace RS, Lambris JD, Gros P.; ''Structures of C3b in complex with factors B and D give insight into complement convertase formation.''; PubMed Europe PMC Scholia
Smith CA, Pangburn MK, Vogel CW, Müller-Eberhard HJ.; ''Molecular architecture of human properdin, a positive regulator of the alternative pathway of complement.''; PubMed Europe PMC Scholia
Gout E, Garlatti V, Smith DF, Lacroix M, Dumestre-Pérard C, Lunardi T, Martin L, Cesbron JY, Arlaud GJ, Gaboriaud C, Thielens NM.; ''Carbohydrate recognition properties of human ficolins: glycan array screening reveals the sialic acid binding specificity of M-ficolin.''; PubMed Europe PMC Scholia
Honoré C, Rørvig S, Munthe-Fog L, Hummelshøj T, Madsen HO, Borregaard N, Garred P.; ''The innate pattern recognition molecule Ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma.''; PubMed Europe PMC Scholia
Christmas SE, Christmas SE, de la Mata Espinosa CT, Halliday D, Buxton CA, Cummerson JA, Johnson PM.; ''Levels of expression of complement regulatory proteins CD46, CD55 and CD59 on resting and activated human peripheral blood leucocytes.''; PubMed Europe PMC Scholia
Sim RB, Laich A.; ''Serine proteases of the complement system.''; PubMed Europe PMC Scholia
Ames RS, Li Y, Sarau HM, Nuthulaganti P, Foley JJ, Ellis C, Zeng Z, Su K, Jurewicz AJ, Hertzberg RP, Bergsma DJ, Kumar C.; ''Molecular cloning and characterization of the human anaphylatoxin C3a receptor.''; PubMed Europe PMC Scholia
Dodds AW, Ren XD, Willis AC, Law SK.; ''The reaction mechanism of the internal thioester in the human complement component C4.''; PubMed Europe PMC Scholia
Arlaud GJ, Reboul A, Sim RB, Colomb MG.; ''Interaction of C1-inhibitor with the C1r and C1s subcomponents in human C1.''; PubMed Europe PMC Scholia

History

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Revision	Action	Time	User	Comment
115062	view	17:00, 25 January 2021	ReactomeTeam	Reactome version 75
113506	view	11:58, 2 November 2020	ReactomeTeam	Reactome version 74
112706	view	16:10, 9 October 2020	ReactomeTeam	Reactome version 73
101621	view	11:49, 1 November 2018	ReactomeTeam	reactome version 66
101157	view	21:35, 31 October 2018	ReactomeTeam	reactome version 65
100683	view	20:08, 31 October 2018	ReactomeTeam	reactome version 64
100233	view	16:53, 31 October 2018	ReactomeTeam	reactome version 63
99785	view	15:18, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
99338	view	12:47, 31 October 2018	ReactomeTeam	reactome version 62
93740	view	13:33, 16 August 2017	ReactomeTeam	reactome version 61
93254	view	11:18, 9 August 2017	ReactomeTeam	reactome version 61
86332	view	09:15, 11 July 2016	ReactomeTeam	reactome version 56
83391	view	11:06, 18 November 2015	ReactomeTeam	Version54
81582	view	13:07, 21 August 2015	ReactomeTeam	Version53
77042	view	08:34, 17 July 2014	ReactomeTeam	Fixed remaining interactions
76747	view	12:11, 16 July 2014	ReactomeTeam	Fixed remaining interactions
76072	view	10:13, 11 June 2014	ReactomeTeam	Re-fixing comment source
75782	view	11:30, 10 June 2014	ReactomeTeam	Reactome 48 Update
75419	view	10:07, 29 May 2014	Lifish	Modified description
75132	view	14:08, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
74779	view	08:52, 30 April 2014	ReactomeTeam	Reactome46
44996	view	14:41, 6 October 2011	MartijnVanIersel	Ontology Term : 'signaling pathway in the innate immune response' added !
42021	view	21:50, 4 March 2011	MaintBot	Automatic update
39824	view	05:51, 21 January 2011	MaintBot	New pathway

External references

DataNodes

View all...

Name	Type	Database reference	Comment
1,3-beta-D-glucan	Metabolite	CHEBI:37671 (ChEBI)
11xCbxE-PROS1	Protein	P07225 (Uniprot-TrEMBL)
11xCbxE-PROS1	Protein	P07225 (Uniprot-TrEMBL)
?FI:CD46, CR1:C4b, C3b complexes	Complex	R-HSA-977599 (Reactome)
Antigen		R-NUL-173548 (Reactome)
Antigen: antibody: C1 (activated C1R and C1S) complex	Complex	R-HSA-173618 (Reactome)
Antigen: antibody: C1 (activated C1R) complex	Complex	R-HSA-173619 (Reactome)
Antigen: antibody: C1 complex	Complex	R-HSA-173582 (Reactome)
Bacterial mannose-based carbohydrate surface pattern		R-NUL-166718 (Reactome)
Bacterial mannose-based carbohydrate surface pattern		R-NUL-166718 (Reactome)
C-reactive protein pentamer:phosphocholine:C1Q	Complex	R-HSA-976769 (Reactome)
C1QA	Protein	P02745 (Uniprot-TrEMBL)
C1QB	Protein	P02746 (Uniprot-TrEMBL)
C1QC	Protein	P02747 (Uniprot-TrEMBL)
C1R C-terminal fragment	Protein	P00736 (Uniprot-TrEMBL)
C1R N-terminal fragment	Protein	P00736 (Uniprot-TrEMBL)
C1R(18-705)	Protein	P00736 (Uniprot-TrEMBL)
C1S C-terminal fragment	Protein	P09871 (Uniprot-TrEMBL)
C1S N-terminal fragment	Protein	P09871 (Uniprot-TrEMBL)
C1S(16-688)	Protein	P09871 (Uniprot-TrEMBL)
C2	Protein	P06681 (Uniprot-TrEMBL)
C2a	Protein	P06681 (Uniprot-TrEMBL)
C2a	Protein	P06681 (Uniprot-TrEMBL)
C2b	Protein	P06681 (Uniprot-TrEMBL)
C3 alpha chain	Protein	P01024 (Uniprot-TrEMBL)
C3 beta chain	Protein	P01024 (Uniprot-TrEMBL)
C3 convertases		R-HSA-173750 (Reactome)
C3(H2O):Bb	Complex	R-HSA-182451 (Reactome)
C3(H2O):CFB	Complex	R-HSA-182529 (Reactome)
C3(H2O)	Complex	R-HSA-182450 (Reactome)
C3a	Protein	P01024 (Uniprot-TrEMBL)
C3b alpha'	Protein	P01024 (Uniprot-TrEMBL)
C3b:Bb:C3b:Properdin	Complex	R-HSA-174554 (Reactome)
C3b	Complex	R-HSA-166832 (Reactome)	Linked by disulphide bond between positions 559 and 816.
C3c alpha' chain fragment 1	Protein	P01024 (Uniprot-TrEMBL)
C3c alpha' chain fragment 1 precursor	Protein	P01024 (Uniprot-TrEMBL)
C3c alpha' chain fragment 2	Protein	P01024 (Uniprot-TrEMBL)
C3c	Complex	R-HSA-3266497 (Reactome)
C3dg	Protein	P01024 (Uniprot-TrEMBL)
C3f	Protein	P01024 (Uniprot-TrEMBL)
C3f	Protein	P01024 (Uniprot-TrEMBL)
C4 activator		R-HSA-166763 (Reactome)
C4 alpha	Protein	P0C0L4 (Uniprot-TrEMBL)	C4 alpha chain has a thioester bond between Cys 1010 and Gln 1013
C4 binding protein:C4bC2a	Complex	R-HSA-981663 (Reactome)
C4 binding protein:protein S	Complex	R-HSA-981655 (Reactome)
C4-binding protein:C4b	Complex	R-HSA-981642 (Reactome)
C4A alpha b	Protein	P0C0L4 (Uniprot-TrEMBL)	C4 alpha chain has a thioester bond between Cys 1010 and Gln 1013
C4A alpha3	Protein	P0C0L4 (Uniprot-TrEMBL)
C4A alpha4 fragment	Protein	P0C0L4 (Uniprot-TrEMBL)
C4A beta	Protein	P0C0L4 (Uniprot-TrEMBL)
C4A gamma	Protein	P0C0L4 (Uniprot-TrEMBL)
C4B alpha	Protein	P0C0L5 (Uniprot-TrEMBL)
C4B alpha chain fragment b	Protein	P0C0L5 (Uniprot-TrEMBL)
C4B alpha3	Protein	P0C0L5 (Uniprot-TrEMBL)
C4B alpha4 fragment	Protein	P0C0L5 (Uniprot-TrEMBL)
C4B beta	Protein	P0C0L5 (Uniprot-TrEMBL)
C4B gamma	Protein	P0C0L5 (Uniprot-TrEMBL)
C4BPA	Protein	P04003 (Uniprot-TrEMBL)
C4BPB	Protein	P20851 (Uniprot-TrEMBL)
C4a	Protein	R-HSA-981725 (Reactome)
C4b with hydrolysed thioester	Complex	R-HSA-2855046 (Reactome)
C4b, C3b	Complex	R-HSA-977600 (Reactome)
C4b-binding protein:Factor I	Complex	R-HSA-981633 (Reactome)
C4b-binding protein	Complex	R-HSA-981649 (Reactome)
C4b:C2a:C3b	Complex	R-HSA-173635 (Reactome)
C4bC2a, C3bBb	Complex	R-HSA-977357 (Reactome)
C4c		R-HSA-981715 (Reactome)
C4c, C3f	Complex	R-HSA-977621 (Reactome)
C4c	Complex	R-HSA-981715 (Reactome)
C4d, iC3b	Protein	R-HSA-977624 (Reactome)
C4d	Protein	R-HSA-981702 (Reactome)
C5 alpha	Protein	P01031 (Uniprot-TrEMBL)
C5 beta	Protein	P01031 (Uniprot-TrEMBL)
C5 convertases		R-HSA-173759 (Reactome)
C5a	Protein	P01031 (Uniprot-TrEMBL)
C5b alpha'	Protein	P01031 (Uniprot-TrEMBL)
C5b:C6 complex	Complex	R-HSA-173711 (Reactome)
C5b:C6:C7 complex	Complex	R-HSA-173708 (Reactome)
C5b:C6:C7 complex	Complex	R-HSA-173719 (Reactome)
C5b:C6:C7:C8 complex	Complex	R-HSA-173722 (Reactome)
C5b	Complex	R-HSA-173671 (Reactome)	Linked by disulphide bond between positions 559 and 816.
C6	Protein	P13671 (Uniprot-TrEMBL)
C6	Protein	P13671 (Uniprot-TrEMBL)
C7	Protein	P10643 (Uniprot-TrEMBL)
C7	Protein	P10643 (Uniprot-TrEMBL)
C8A	Protein	P07357 (Uniprot-TrEMBL)
C8B	Protein	P07358 (Uniprot-TrEMBL)
C8G	Protein	P07360 (Uniprot-TrEMBL)
C8	Complex	R-HSA-173713 (Reactome)
C9(22-559)	Protein	P02748 (Uniprot-TrEMBL)
C9(22-559)	Protein	P02748 (Uniprot-TrEMBL)
CD46	Protein	P15529 (Uniprot-TrEMBL)
CD46, CR1:C4b:C3b complexes	Complex	R-HSA-981661 (Reactome)
CD46, CR1	Protein	R-HSA-977360 (Reactome)	CR1 and MCP are widely distributed cell surface molecules that bind C4b and C3b, and act as cofactors for Complement factor I, thereby regulating the classical and alternative C3 convertases.
CD46:C3b	Complex	R-HSA-981623 (Reactome)
CD46:C4b	Complex	R-HSA-981669 (Reactome)
CD46	Protein	P15529 (Uniprot-TrEMBL)
CD55	Protein	P08174 (Uniprot-TrEMBL)
CD55:C3 convertase complexes	Complex	R-HSA-981657 (Reactome)
CD55	Protein	P08174 (Uniprot-TrEMBL)
CD59	Protein	P13987 (Uniprot-TrEMBL)
CD59:C5b-C9	Complex	R-HSA-2530426 (Reactome)
CD59	Protein	P13987 (Uniprot-TrEMBL)
CFB(26-259)	Protein	P00751 (Uniprot-TrEMBL)
CFB(26-764)	Protein	P00751 (Uniprot-TrEMBL)
CFB(26-764)	Protein	P00751 (Uniprot-TrEMBL)
CFB(260-764)	Protein	P00751 (Uniprot-TrEMBL)
CFB(260-764)	Protein	P00751 (Uniprot-TrEMBL)
CFD	Protein	P00746 (Uniprot-TrEMBL)
CFH	Protein	P08603 (Uniprot-TrEMBL)
CFH, FHR-3	Protein	R-HSA-2109537 (Reactome)
CFH:C3b	Complex	R-HSA-976755 (Reactome)
CFH:Host cell surface	Complex	R-HSA-1006173 (Reactome)
CFH	Protein	P08603 (Uniprot-TrEMBL)
CFHR3	Protein	Q02985 (Uniprot-TrEMBL)
CFI(19-335)	Protein	P05156 (Uniprot-TrEMBL)
CFI(19-335)	Protein	P05156 (Uniprot-TrEMBL)
CFI(340-583)	Protein	P05156 (Uniprot-TrEMBL)
CFI(340-583)	Protein	P05156 (Uniprot-TrEMBL)
CFI:CFH,FHR3:C3b	Complex	R-HSA-977365 (Reactome)
CFI:CFH:C3b	Complex	R-HSA-976770 (Reactome)
CFI	Complex	R-HSA-976749 (Reactome)
CR1	Protein	P17927 (Uniprot-TrEMBL)
CR1:C3bBb, C4bC2a complexes	Complex	R-HSA-981676 (Reactome)
CR1:C3b	Complex	R-HSA-981635 (Reactome)
CR1:C4b	Complex	R-HSA-981675 (Reactome)
CR1:iC3b	Complex	R-HSA-3266508 (Reactome)
CR1	Protein	P17927 (Uniprot-TrEMBL)
CRP(19-224)	Protein	P02741 (Uniprot-TrEMBL)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Ca2+	Metabolite	CHEBI:29108 (ChEBI)
Cell surface:C3b:Bb:Properdin	Complex	R-HSA-173752 (Reactome)
Cell surface:CFH,FHR3:C3bBb	Complex	R-HSA-977373 (Reactome)
Cell surface:FH,FHR3:C3b	Complex	R-HSA-977596 (Reactome)
Cell surface		R-NUL-983438 (Reactome)	This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Cell surface:C3b:Bb	Complex	R-HSA-173749 (Reactome)
Cell surface:C3b:CFB	Complex	R-HSA-173737 (Reactome)
Cell surface:C3b	Complex	R-HSA-981542 (Reactome)
Cell surface:C4b:C2a	Complex	R-HSA-166784 (Reactome)
Cell surface:C4b	Complex	R-HSA-981716 (Reactome)
Cell surface		R-NUL-983438 (Reactome)	This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.
Complement Factor 4	Complex	R-HSA-981697 (Reactome)
Complement factor 3	Complex	R-HSA-166822 (Reactome)	Linked by disulphide bond between positions 559 and 816.
Complement factor 5	Complex	R-HSA-173676 (Reactome)
Complement factor D	Protein	R-HSA-2975824 (Reactome)	This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
D-fucose	Metabolite	CHEBI:28847 (ChEBI)
DAF:C3b	Complex	R-HSA-981684 (Reactome)
DAF:C4b	Complex	R-HSA-981639 (Reactome)
FCN1	Protein	O00602 (Uniprot-TrEMBL)
FCN1 ligand	Metabolite	R-ALL-2855114 (Reactome)
FCN1:MASP2 dimer:MASP1 dimer	Complex	R-HSA-2855100 (Reactome)
FCN1:MASPs:Ca2+:FCN1 ligand	Complex	R-HSA-2855134 (Reactome)
FCN2	Protein	Q15485 (Uniprot-TrEMBL)
FCN2 ligand	Metabolite	R-ALL-2855063 (Reactome)
FCN2:MASP2 dimer:MASP1 dimer	Complex	R-HSA-2855087 (Reactome)
FCN2:MASPs:Ca2+:FCN2 ligand	Complex	R-HSA-2855065 (Reactome)
FCN3	Protein	O75636 (Uniprot-TrEMBL)
FCN3 ligand	Metabolite	R-ALL-2855098 (Reactome)
FCN3:MASP2 dimer:MASP1 dimer	Complex	R-HSA-2855122 (Reactome)
FCN3:MASPs:Ca2+:FCN3 ligand	Complex	R-HSA-2855093 (Reactome)
H2O	Metabolite	CHEBI:15377 (ChEBI)
Heparins	Metabolite	CHEBI:24505 (ChEBI)
Host cell surface	Complex	R-HSA-1006146 (Reactome)
IGHG1	Protein	P01857 (Uniprot-TrEMBL)
IGHG2	Protein	P01859 (Uniprot-TrEMBL)
IGHG3	Protein	P01860 (Uniprot-TrEMBL)
IGHG4	Protein	P01861 (Uniprot-TrEMBL)
IGHV(1-?)	Protein	A2KUC3 (Uniprot-TrEMBL)
IGHV7-81(1-?)	Protein	Q6PIL0 (Uniprot-TrEMBL)
IGKC	Protein	P01834 (Uniprot-TrEMBL)
IGKV1-5(23-?)	Protein	P01602 (Uniprot-TrEMBL)
IGKV4-1(21-?)	Protein	P06312 (Uniprot-TrEMBL)
IGKVA18(21-?)	Protein	A2NJV5 (Uniprot-TrEMBL)
IGLC1	Protein	P0CG04 (Uniprot-TrEMBL)
IGLC2	Protein	P0CG05 (Uniprot-TrEMBL)
IGLC3	Protein	P0CG06 (Uniprot-TrEMBL)
IGLC6	Protein	P0CF74 (Uniprot-TrEMBL)
IGLC7	Protein	A0M8Q6 (Uniprot-TrEMBL)
IGLV(23-?)	Protein	A2NXD2 (Uniprot-TrEMBL)
IGLV1-36(1-?)	Protein	Q5NV67 (Uniprot-TrEMBL)
IGLV1-40(1-?)	Protein	Q5NV69 (Uniprot-TrEMBL)
IGLV1-44(1-?)	Protein	Q5NV81 (Uniprot-TrEMBL)
IGLV10-54(1-?)	Protein	Q5NV86 (Uniprot-TrEMBL)
IGLV11-55(1-?)	Protein	Q5NV87 (Uniprot-TrEMBL)
IGLV2-11(1-?)	Protein	Q5NV84 (Uniprot-TrEMBL)
IGLV2-18(1-?)	Protein	Q5NV65 (Uniprot-TrEMBL)
IGLV2-23(1-?)	Protein	Q5NV89 (Uniprot-TrEMBL)
IGLV2-33(1-?)	Protein	Q5NV66 (Uniprot-TrEMBL)
IGLV3-12(1-?)	Protein	Q5NV85 (Uniprot-TrEMBL)
IGLV3-16(1-?)	Protein	Q5NV64 (Uniprot-TrEMBL)
IGLV3-22(1-?)	Protein	Q5NV75 (Uniprot-TrEMBL)
IGLV3-25(1-?)	Protein	Q5NV90 (Uniprot-TrEMBL)
IGLV3-27(1-?)	Protein	Q5NV91 (Uniprot-TrEMBL)
IGLV4-3(1-?)	Protein	Q5NV61 (Uniprot-TrEMBL)
IGLV4-60(1-?)	Protein	Q5NV79 (Uniprot-TrEMBL)
IGLV4-69(1-?)	Protein	Q5NV92 (Uniprot-TrEMBL)
IGLV5-37(1-?)	Protein	Q5NV68 (Uniprot-TrEMBL)
IGLV5-45(1-?)	Protein	Q5NV82 (Uniprot-TrEMBL)
IGLV7-43(1-?)	Protein	Q5NV80 (Uniprot-TrEMBL)
IGLV7-46(1-?)	Protein	Q5NV83 (Uniprot-TrEMBL)
IGLV8-61(1-?)	Protein	Q5NV62 (Uniprot-TrEMBL)
Ig heavy chain V-I region EU	Protein	P01742 (Uniprot-TrEMBL)
Ig heavy chain V-I region HG3	Protein	P01743 (Uniprot-TrEMBL)
Ig heavy chain V-I region Mot	Protein	P06326 (Uniprot-TrEMBL)
Ig heavy chain V-I region ND	Protein	P01744 (Uniprot-TrEMBL)
Ig heavy chain V-I region SIE	Protein	P01761 (Uniprot-TrEMBL)
Ig heavy chain V-I region WOL	Protein	P01760 (Uniprot-TrEMBL)
Ig heavy chain V-II region ARH-77	Protein	P06331 (Uniprot-TrEMBL)
Ig heavy chain V-II region COR	Protein	P01815 (Uniprot-TrEMBL)
Ig heavy chain V-II region DAW	Protein	P01816 (Uniprot-TrEMBL)
Ig heavy chain V-II region HE	Protein	P01818 (Uniprot-TrEMBL)
Ig heavy chain V-II region MCE	Protein	P01817 (Uniprot-TrEMBL)
Ig heavy chain V-II region NEWM	Protein	P01825 (Uniprot-TrEMBL)
Ig heavy chain V-II region OU	Protein	P01814 (Uniprot-TrEMBL)
Ig heavy chain V-II region SESS	Protein	P04438 (Uniprot-TrEMBL)
Ig heavy chain V-II region WAH	Protein	P01824 (Uniprot-TrEMBL)
Ig heavy chain V-III region BRO	Protein	P01766 (Uniprot-TrEMBL)
Ig heavy chain V-III region BUR	Protein	P01773 (Uniprot-TrEMBL)
Ig heavy chain V-III region BUT	Protein	P01767 (Uniprot-TrEMBL)
Ig heavy chain V-III region CAM	Protein	P01768 (Uniprot-TrEMBL)
Ig heavy chain V-III region DOB	Protein	P01782 (Uniprot-TrEMBL)
Ig heavy chain V-III region GA	Protein	P01769 (Uniprot-TrEMBL)
Ig heavy chain V-III region GAL	Protein	P01781 (Uniprot-TrEMBL)
Ig heavy chain V-III region HIL	Protein	P01771 (Uniprot-TrEMBL)
Ig heavy chain V-III region JON	Protein	P01780 (Uniprot-TrEMBL)
Ig heavy chain V-III region KOL	Protein	P01772 (Uniprot-TrEMBL)
Ig heavy chain V-III region LAY	Protein	P01775 (Uniprot-TrEMBL)
Ig heavy chain V-III region NIE	Protein	P01770 (Uniprot-TrEMBL)
Ig heavy chain V-III region POM	Protein	P01774 (Uniprot-TrEMBL)
Ig heavy chain V-III region TEI	Protein	P01777 (Uniprot-TrEMBL)
Ig heavy chain V-III region TIL	Protein	P01765 (Uniprot-TrEMBL)
Ig heavy chain V-III region TRO	Protein	P01762 (Uniprot-TrEMBL)
Ig heavy chain V-III region TUR	Protein	P01779 (Uniprot-TrEMBL)
Ig heavy chain V-III region WAS	Protein	P01776 (Uniprot-TrEMBL)
Ig heavy chain V-III region WEA	Protein	P01763 (Uniprot-TrEMBL)
Ig heavy chain V-III region ZAP	Protein	P01778 (Uniprot-TrEMBL)
Ig kappa chain V region EV15	Protein	P06315 (Uniprot-TrEMBL)
Ig kappa chain V-I region AG	Protein	P01593 (Uniprot-TrEMBL)
Ig kappa chain V-I region AU	Protein	P01594 (Uniprot-TrEMBL)
Ig kappa chain V-I region BAN	Protein	P04430 (Uniprot-TrEMBL)
Ig kappa chain V-I region Bi	Protein	P01595 (Uniprot-TrEMBL)
Ig kappa chain V-I region CAR	Protein	P01596 (Uniprot-TrEMBL)
Ig kappa chain V-I region DEE	Protein	P01597 (Uniprot-TrEMBL)
Ig kappa chain V-I region Daudi	Protein	P04432 (Uniprot-TrEMBL)
Ig kappa chain V-I region EU	Protein	P01598 (Uniprot-TrEMBL)
Ig kappa chain V-I region Gal	Protein	P01599 (Uniprot-TrEMBL)
Ig kappa chain V-I region HK101	Protein	P01601 (Uniprot-TrEMBL)
Ig kappa chain V-I region Hau	Protein	P01600 (Uniprot-TrEMBL)
Ig kappa chain V-I region Ka	Protein	P01603 (Uniprot-TrEMBL)
Ig kappa chain V-I region Kue	Protein	P01604 (Uniprot-TrEMBL)
Ig kappa chain V-I region Lay	Protein	P01605 (Uniprot-TrEMBL)
Ig kappa chain V-I region Mev	Protein	P01612 (Uniprot-TrEMBL)
Ig kappa chain V-I region Ni	Protein	P01613 (Uniprot-TrEMBL)
Ig kappa chain V-I region OU	Protein	P01606 (Uniprot-TrEMBL)
Ig kappa chain V-I region Rei	Protein	P01607 (Uniprot-TrEMBL)
Ig kappa chain V-I region Roy	Protein	P01608 (Uniprot-TrEMBL)
Ig kappa chain V-I region Scw	Protein	P01609 (Uniprot-TrEMBL)
Ig kappa chain V-I region WAT	Protein	P80362 (Uniprot-TrEMBL)
Ig kappa chain V-I region WEA	Protein	P01610 (Uniprot-TrEMBL)
Ig kappa chain V-I region Walker	Protein	P04431 (Uniprot-TrEMBL)
Ig kappa chain V-I region Wes	Protein	P01611 (Uniprot-TrEMBL)
Ig kappa chain V-II region Cum	Protein	P01614 (Uniprot-TrEMBL)
Ig kappa chain V-II region FR	Protein	P01615 (Uniprot-TrEMBL)
Ig kappa chain V-II region GM607	Protein	P06309 (Uniprot-TrEMBL)
Ig kappa chain V-II region MIL	Protein	P01616 (Uniprot-TrEMBL)
Ig kappa chain V-II region RPMI 6410	Protein	P06310 (Uniprot-TrEMBL)
Ig kappa chain V-II region TEW	Protein	P01617 (Uniprot-TrEMBL)
Ig kappa chain V-III region B6	Protein	P01619 (Uniprot-TrEMBL)
Ig kappa chain V-III region CLL	Protein	P04207 (Uniprot-TrEMBL)
Ig kappa chain V-III region GOL	Protein	P04206 (Uniprot-TrEMBL)
Ig kappa chain V-III region HAH	Protein	P18135 (Uniprot-TrEMBL)
Ig kappa chain V-III region HIC	Protein	P18136 (Uniprot-TrEMBL)
Ig kappa chain V-III region IARC/BL41	Protein	P06311 (Uniprot-TrEMBL)
Ig kappa chain V-III region NG9	Protein	P01621 (Uniprot-TrEMBL)
Ig kappa chain V-III region POM	Protein	P01624 (Uniprot-TrEMBL)
Ig kappa chain V-III region SIE	Protein	P01620 (Uniprot-TrEMBL)
Ig kappa chain V-III region Ti	Protein	P01622 (Uniprot-TrEMBL)
Ig kappa chain V-III region VG	Protein	P04433 (Uniprot-TrEMBL)
Ig kappa chain V-III region VH	Protein	P04434 (Uniprot-TrEMBL)
Ig kappa chain V-III region WOL	Protein	P01623 (Uniprot-TrEMBL)
Ig kappa chain V-IV region B17	Protein	P06314 (Uniprot-TrEMBL)
Ig kappa chain V-IV region JI	Protein	P06313 (Uniprot-TrEMBL)
Ig kappa chain V-IV region Len	Protein	P01625 (Uniprot-TrEMBL)
Ig kappa chain V-IV region STH	Protein	P83593 (Uniprot-TrEMBL)
Ig lambda chain V region 4A	Protein	P04211 (Uniprot-TrEMBL)
Ig lambda chain V-I region BL2	Protein	P06316 (Uniprot-TrEMBL)
Ig lambda chain V-I region EPS	Protein	P06888 (Uniprot-TrEMBL)
Ig lambda chain V-I region HA	Protein	P01700 (Uniprot-TrEMBL)
Ig lambda chain V-I region MEM	Protein	P06887 (Uniprot-TrEMBL)
Ig lambda chain V-I region NEW	Protein	P01701 (Uniprot-TrEMBL)
Ig lambda chain V-I region NEWM	Protein	P01703 (Uniprot-TrEMBL)
Ig lambda chain V-I region NIG-64	Protein	P01702 (Uniprot-TrEMBL)
Ig lambda chain V-I region VOR	Protein	P01699 (Uniprot-TrEMBL)
Ig lambda chain V-I region WAH	Protein	P04208 (Uniprot-TrEMBL)
Ig lambda chain V-II region BO	Protein	P01710 (Uniprot-TrEMBL)
Ig lambda chain V-II region BOH	Protein	P01706 (Uniprot-TrEMBL)
Ig lambda chain V-II region BUR	Protein	P01708 (Uniprot-TrEMBL)
Ig lambda chain V-II region MGC	Protein	P01709 (Uniprot-TrEMBL)
Ig lambda chain V-II region NEI	Protein	P01705 (Uniprot-TrEMBL)
Ig lambda chain V-II region NIG-58	Protein	P01713 (Uniprot-TrEMBL)
Ig lambda chain V-II region NIG-84	Protein	P04209 (Uniprot-TrEMBL)
Ig lambda chain V-II region TOG	Protein	P01704 (Uniprot-TrEMBL)
Ig lambda chain V-II region TRO	Protein	P01707 (Uniprot-TrEMBL)
Ig lambda chain V-II region VIL	Protein	P01711 (Uniprot-TrEMBL)
Ig lambda chain V-II region WIN	Protein	P01712 (Uniprot-TrEMBL)
Ig lambda chain V-III region LOI	Protein	P80748 (Uniprot-TrEMBL)
Ig lambda chain V-III region SH	Protein	P01714 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Bau	Protein	P01715 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Hil	Protein	P01717 (Uniprot-TrEMBL)
Ig lambda chain V-IV region Kern	Protein	P01718 (Uniprot-TrEMBL)
Ig lambda chain V-IV region MOL	Protein	P06889 (Uniprot-TrEMBL)
Ig lambda chain V-IV region X	Protein	P01716 (Uniprot-TrEMBL)
Ig lambda chain V-V region DEL	Protein	P01719 (Uniprot-TrEMBL)
Ig lambda chain V-VI region AR	Protein	P01721 (Uniprot-TrEMBL)
Ig lambda chain V-VI region EB4	Protein	P06319 (Uniprot-TrEMBL)
Ig lambda chain V-VI region NIG-48	Protein	P01722 (Uniprot-TrEMBL)
Ig lambda chain V-VI region SUT	Protein	P06317 (Uniprot-TrEMBL)
Ig lambda chain V-VI region WLT	Protein	P06318 (Uniprot-TrEMBL)
Ig lambda chain V-VII region MOT	Protein	P01720 (Uniprot-TrEMBL)
IgH heavy chain V-III region VH26 precursor	Protein	P01764 (Uniprot-TrEMBL)
Lipoteichoic acid	Metabolite	CHEBI:28640 (ChEBI)
MASP1(20-448)	Protein	P48740 (Uniprot-TrEMBL)
MASP1(20-699)	Protein	P48740 (Uniprot-TrEMBL)
MASP1(449-699)	Protein	P48740 (Uniprot-TrEMBL)
MASP2-1	Protein	O00187-1 (Uniprot-TrEMBL)
MASP2-1(16-444)	Protein	O00187-1 (Uniprot-TrEMBL)
MASP2-1(445-686)	Protein	O00187-1 (Uniprot-TrEMBL)
MBL bound to mannose-based carbohydrates on bacterial surfaces	Complex	R-HSA-166719 (Reactome)
MBL-II:MASP-2 dimer:MASP-1 dimer complex	Complex	R-HSA-166710 (Reactome)
MBL/FCN:activated MASP:carbohydrate patterns	Complex	R-HSA-3266545 (Reactome)
MBL/Ficolin:MASPs bound to carbohydrate patterns	Complex	R-HSA-3266540 (Reactome)
MBL2	Protein	P11226 (Uniprot-TrEMBL)
MBL:activated MASPs:mannose-based carbohydrates	Complex	R-HSA-166724 (Reactome)
Membrane Attack Complex	Complex	R-HSA-173728 (Reactome)
N-acetyl-D-glucosamine	Metabolite	CHEBI:28009 (ChEBI)
N-acetylgalactosamine	Metabolite	CHEBI:40356 (ChEBI)
PCho	Metabolite	CHEBI:36700 (ChEBI)
Properdin oligomer		R-HSA-182548 (Reactome)
Properdin oligomer		R-HSA-182548 (Reactome)
Sialic acid	Metabolite	CHEBI:28879 (ChEBI)
VTN	Protein	P04004 (Uniprot-TrEMBL)
VTN:C5b:C6:C7:C8:C9	Complex	R-HSA-2530442 (Reactome)
VTN:C5b:C6:C7	Complex	R-HSA-2530437 (Reactome)
VTN	Protein	P04004 (Uniprot-TrEMBL)
dNQ-C3(672-1663)	Protein	P01024 (Uniprot-TrEMBL)
dNQ-C4A(757-1446)	Protein	P0C0L4 (Uniprot-TrEMBL)
dNQ-C4B(757-1446)	Protein	P0C0L5 (Uniprot-TrEMBL)
iC3b	Complex	R-HSA-976805 (Reactome)
iC3b	Complex	R-HSA-977380 (Reactome)
thioester-C1010-Q1013-C4b	Complex	R-HSA-981700 (Reactome)

Annotated Interactions

View all...

Source	Target	Type	Database reference	Comment
11xCbxE-PROS1			R-HSA-981665 (Reactome)
	?FI:CD46, CR1:C4b, C3b complexes	Arrow	R-HSA-977602 (Reactome)
?FI:CD46, CR1:C4b, C3b complexes			R-HSA-977615 (Reactome)
?FI:CD46, CR1:C4b, C3b complexes		mim-catalysis	R-HSA-977615 (Reactome)
	Antigen: antibody: C1 (activated C1R and C1S) complex	Arrow	R-HSA-173631 (Reactome)
	Antigen: antibody: C1 (activated C1R) complex	Arrow	R-HSA-173626 (Reactome)
Antigen: antibody: C1 (activated C1R) complex			R-HSA-173631 (Reactome)
Antigen: antibody: C1 (activated C1R) complex		mim-catalysis	R-HSA-173631 (Reactome)
Antigen: antibody: C1 complex			R-HSA-173626 (Reactome)
Antigen: antibody: C1 complex		mim-catalysis	R-HSA-173626 (Reactome)
Bacterial mannose-based carbohydrate surface pattern			R-HSA-166721 (Reactome)
C-reactive protein pentamer:phosphocholine:C1Q		Arrow	R-HSA-173626 (Reactome)
C2			R-HSA-166792 (Reactome)
	C2a	Arrow	R-HSA-166792 (Reactome)
	C2a	Arrow	R-HSA-977619 (Reactome)
	C2a	Arrow	R-HSA-977629 (Reactome)
	C2a	Arrow	R-HSA-981621 (Reactome)
	C2a	Arrow	R-HSA-981680 (Reactome)
C2a			R-HSA-166795 (Reactome)
	C2b	Arrow	R-HSA-166792 (Reactome)
C3 convertases			R-HSA-981621 (Reactome)
C3 convertases		mim-catalysis	R-HSA-166817 (Reactome)
	C3(H2O):Bb	Arrow	R-HSA-173745 (Reactome)
C3(H2O):Bb		mim-catalysis	R-HSA-183130 (Reactome)
	C3(H2O):CFB	Arrow	R-HSA-173740 (Reactome)
C3(H2O):CFB			R-HSA-173745 (Reactome)
	C3(H2O)	Arrow	R-HSA-173739 (Reactome)
	C3(H2O)	Arrow	R-HSA-981621 (Reactome)
C3(H2O)			R-HSA-173740 (Reactome)
	C3a	Arrow	R-HSA-166817 (Reactome)
	C3a	Arrow	R-HSA-174551 (Reactome)
	C3a	Arrow	R-HSA-183130 (Reactome)
	C3b:Bb:C3b:Properdin	Arrow	R-HSA-174551 (Reactome)
	C3b	Arrow	R-HSA-166817 (Reactome)
	C3b	Arrow	R-HSA-183130 (Reactome)
	C3b	Arrow	R-HSA-981621 (Reactome)
C3b			R-HSA-976768 (Reactome)
C3b			R-HSA-981539 (Reactome)
	C3c	Arrow	R-HSA-3266557 (Reactome)
	C3dg	Arrow	R-HSA-3266557 (Reactome)
	C3f	Arrow	R-HSA-976743 (Reactome)
	C3f	Arrow	R-HSA-977371 (Reactome)
C4 activator		mim-catalysis	R-HSA-166753 (Reactome)
C4 activator		mim-catalysis	R-HSA-166792 (Reactome)
	C4 binding protein:C4bC2a	Arrow	R-HSA-981648 (Reactome)
C4 binding protein:C4bC2a			R-HSA-981680 (Reactome)
	C4 binding protein:protein S	Arrow	R-HSA-981665 (Reactome)
	C4-binding protein:C4b	Arrow	R-HSA-977626 (Reactome)
	C4-binding protein:C4b	Arrow	R-HSA-981680 (Reactome)
C4-binding protein:C4b			R-HSA-981658 (Reactome)
	C4a	Arrow	R-HSA-166753 (Reactome)
	C4b with hydrolysed thioester	Arrow	R-HSA-2855047 (Reactome)
C4b, C3b			R-HSA-1006143 (Reactome)
	C4b-binding protein:Factor I	Arrow	R-HSA-981658 (Reactome)
C4b-binding protein:Factor I			R-HSA-981637 (Reactome)
	C4b-binding protein	Arrow	R-HSA-981637 (Reactome)
C4b-binding protein			R-HSA-977626 (Reactome)
C4b-binding protein			R-HSA-981648 (Reactome)
C4b-binding protein			R-HSA-981665 (Reactome)
	C4b:C2a:C3b	Arrow	R-HSA-173636 (Reactome)
C4bC2a, C3bBb			R-HSA-977375 (Reactome)
C4bC2a, C3bBb			R-HSA-981535 (Reactome)
	C4c, C3f	Arrow	R-HSA-977615 (Reactome)
	C4c	Arrow	R-HSA-981637 (Reactome)
	C4d, iC3b	Arrow	R-HSA-977615 (Reactome)
	C4d	Arrow	R-HSA-981637 (Reactome)
C5 convertases		mim-catalysis	R-HSA-173680 (Reactome)
	C5a	Arrow	R-HSA-173680 (Reactome)
	C5b:C6 complex	Arrow	R-HSA-173705 (Reactome)
C5b:C6 complex			R-HSA-173709 (Reactome)
	C5b:C6:C7 complex	Arrow	R-HSA-173709 (Reactome)
	C5b:C6:C7 complex	Arrow	R-HSA-173720 (Reactome)
C5b:C6:C7 complex			R-HSA-173720 (Reactome)
C5b:C6:C7 complex			R-HSA-173723 (Reactome)
C5b:C6:C7 complex			R-HSA-2530453 (Reactome)
	C5b:C6:C7:C8 complex	Arrow	R-HSA-173723 (Reactome)
C5b:C6:C7:C8 complex			R-HSA-173725 (Reactome)
C5b:C6:C7:C8 complex			R-HSA-2530445 (Reactome)
	C5b	Arrow	R-HSA-173680 (Reactome)
C5b			R-HSA-173705 (Reactome)
C6			R-HSA-173705 (Reactome)
C7			R-HSA-173709 (Reactome)
C8			R-HSA-173723 (Reactome)
C8			R-HSA-2530429 (Reactome)
C9(22-559)			R-HSA-173725 (Reactome)
C9(22-559)			R-HSA-2530429 (Reactome)
C9(22-559)			R-HSA-2530445 (Reactome)
CD46, CR1:C4b:C3b complexes			R-HSA-977602 (Reactome)
	CD46, CR1	Arrow	R-HSA-977615 (Reactome)
	CD46:C3b	Arrow	R-HSA-1006143 (Reactome)
	CD46:C4b	Arrow	R-HSA-1006143 (Reactome)
CD46			R-HSA-1006143 (Reactome)
	CD55:C3 convertase complexes	Arrow	R-HSA-981535 (Reactome)
CD55:C3 convertase complexes			R-HSA-977619 (Reactome)
CD55			R-HSA-981535 (Reactome)
	CD59:C5b-C9	Arrow	R-HSA-2530445 (Reactome)
CD59			R-HSA-2530445 (Reactome)
	CFB(26-259)	Arrow	R-HSA-173745 (Reactome)
	CFB(26-259)	Arrow	R-HSA-183122 (Reactome)
CFB(26-764)			R-HSA-173740 (Reactome)
CFB(26-764)			R-HSA-183126 (Reactome)
	CFB(260-764)	Arrow	R-HSA-977605 (Reactome)
	CFB(260-764)	Arrow	R-HSA-977619 (Reactome)
	CFB(260-764)	Arrow	R-HSA-977629 (Reactome)
	CFB(260-764)	Arrow	R-HSA-981621 (Reactome)
	CFH, FHR-3	Arrow	R-HSA-977371 (Reactome)
CFH, FHR-3			R-HSA-977363 (Reactome)
CFH, FHR-3			R-HSA-981728 (Reactome)
	CFH:C3b	Arrow	R-HSA-976768 (Reactome)
CFH:C3b			R-HSA-976810 (Reactome)
	CFH:Host cell surface	Arrow	R-HSA-1006169 (Reactome)
CFH:Host cell surface		Arrow	R-HSA-977363 (Reactome)
CFH:Host cell surface		Arrow	R-HSA-981728 (Reactome)
	CFH	Arrow	R-HSA-976743 (Reactome)
CFH			R-HSA-1006169 (Reactome)
CFH			R-HSA-976768 (Reactome)
CFI(19-335)			R-HSA-976801 (Reactome)
CFI(340-583)			R-HSA-976801 (Reactome)
	CFI:CFH,FHR3:C3b	Arrow	R-HSA-977359 (Reactome)
CFI:CFH,FHR3:C3b			R-HSA-977371 (Reactome)
CFI:CFH,FHR3:C3b		mim-catalysis	R-HSA-977371 (Reactome)
	CFI:CFH:C3b	Arrow	R-HSA-976810 (Reactome)
CFI:CFH:C3b			R-HSA-976743 (Reactome)
CFI:CFH:C3b		mim-catalysis	R-HSA-976743 (Reactome)
	CFI	Arrow	R-HSA-976743 (Reactome)
	CFI	Arrow	R-HSA-976801 (Reactome)
	CFI	Arrow	R-HSA-977371 (Reactome)
	CFI	Arrow	R-HSA-977615 (Reactome)
	CFI	Arrow	R-HSA-981637 (Reactome)
CFI			R-HSA-976810 (Reactome)
CFI			R-HSA-977359 (Reactome)
CFI			R-HSA-977602 (Reactome)
CFI			R-HSA-981658 (Reactome)
	CR1:C3b	Arrow	R-HSA-977629 (Reactome)
	CR1:C3bBb, C4bC2a complexes	Arrow	R-HSA-977375 (Reactome)
CR1:C3bBb, C4bC2a complexes			R-HSA-977629 (Reactome)
	CR1:C4b	Arrow	R-HSA-977629 (Reactome)
CR1:iC3b			R-HSA-3266557 (Reactome)
	CR1	Arrow	R-HSA-3266557 (Reactome)
CR1			R-HSA-977375 (Reactome)
Ca2+			R-HSA-166721 (Reactome)
Ca2+			R-HSA-2855054 (Reactome)
Ca2+			R-HSA-2855077 (Reactome)
Ca2+			R-HSA-2855125 (Reactome)
	Cell surface:C3b:Bb:Properdin	Arrow	R-HSA-173754 (Reactome)
Cell surface:C3b:Bb:Properdin			R-HSA-174551 (Reactome)
Cell surface:C3b:Bb:Properdin		mim-catalysis	R-HSA-174551 (Reactome)
	Cell surface:CFH,FHR3:C3bBb	Arrow	R-HSA-977363 (Reactome)
Cell surface:CFH,FHR3:C3bBb			R-HSA-977605 (Reactome)
	Cell surface:FH,FHR3:C3b	Arrow	R-HSA-977605 (Reactome)
	Cell surface:FH,FHR3:C3b	Arrow	R-HSA-981728 (Reactome)
Cell surface:FH,FHR3:C3b			R-HSA-977359 (Reactome)
	Cell surface:C3b:Bb	Arrow	R-HSA-183122 (Reactome)
Cell surface:C3b:Bb			R-HSA-173754 (Reactome)
Cell surface:C3b:Bb			R-HSA-977363 (Reactome)
	Cell surface:C3b:CFB	Arrow	R-HSA-183126 (Reactome)
Cell surface:C3b:CFB			R-HSA-183122 (Reactome)
	Cell surface:C3b	Arrow	R-HSA-981539 (Reactome)
Cell surface:C3b			R-HSA-173636 (Reactome)
Cell surface:C3b			R-HSA-183126 (Reactome)
Cell surface:C3b			R-HSA-981728 (Reactome)
	Cell surface:C4b:C2a	Arrow	R-HSA-166795 (Reactome)
	Cell surface:C4b:C2a	Arrow	R-HSA-981621 (Reactome)
Cell surface:C4b:C2a			R-HSA-173636 (Reactome)
Cell surface:C4b:C2a			R-HSA-981648 (Reactome)
	Cell surface:C4b	Arrow	R-HSA-981621 (Reactome)
	Cell surface:C4b	Arrow	R-HSA-981713 (Reactome)
Cell surface:C4b			R-HSA-166795 (Reactome)
Cell surface			R-HSA-981539 (Reactome)
Cell surface			R-HSA-981713 (Reactome)
Complement Factor 4			R-HSA-166753 (Reactome)
Complement factor 3			R-HSA-166817 (Reactome)
Complement factor 3			R-HSA-173739 (Reactome)
Complement factor 3			R-HSA-174551 (Reactome)
Complement factor 3			R-HSA-183130 (Reactome)
Complement factor 5			R-HSA-173680 (Reactome)
Complement factor D		mim-catalysis	R-HSA-173745 (Reactome)
Complement factor D		mim-catalysis	R-HSA-183122 (Reactome)
	DAF:C3b	Arrow	R-HSA-977619 (Reactome)
	DAF:C4b	Arrow	R-HSA-977619 (Reactome)
FCN1 ligand			R-HSA-2855125 (Reactome)
FCN1:MASP2 dimer:MASP1 dimer			R-HSA-2855125 (Reactome)
	FCN1:MASPs:Ca2+:FCN1 ligand	Arrow	R-HSA-2855125 (Reactome)
FCN2 ligand			R-HSA-2855054 (Reactome)
FCN2:MASP2 dimer:MASP1 dimer			R-HSA-2855054 (Reactome)
	FCN2:MASPs:Ca2+:FCN2 ligand	Arrow	R-HSA-2855054 (Reactome)
FCN3 ligand			R-HSA-2855077 (Reactome)
FCN3:MASP2 dimer:MASP1 dimer			R-HSA-2855077 (Reactome)
	FCN3:MASPs:Ca2+:FCN3 ligand	Arrow	R-HSA-2855077 (Reactome)
H2O			R-HSA-173739 (Reactome)
H2O			R-HSA-2855047 (Reactome)
Host cell surface			R-HSA-1006169 (Reactome)
	MBL bound to mannose-based carbohydrates on bacterial surfaces	Arrow	R-HSA-166721 (Reactome)
MBL-II:MASP-2 dimer:MASP-1 dimer complex			R-HSA-166721 (Reactome)
	MBL/FCN:activated MASP:carbohydrate patterns	Arrow	R-HSA-166726 (Reactome)
MBL/Ficolin:MASPs bound to carbohydrate patterns			R-HSA-166726 (Reactome)
	Membrane Attack Complex	Arrow	R-HSA-173725 (Reactome)
	Properdin oligomer	Arrow	R-HSA-981621 (Reactome)
Properdin oligomer			R-HSA-173754 (Reactome)
			R-HSA-1006143 (Reactome)	Membrane cofactor protein (MCP; CD46) is a widely distributed C3b/C4b-binding cell surface glycoprotein which is a cofactor for Complement factor I.
			R-HSA-1006169 (Reactome)	Factor H preferentially binds to host cells and surfaces that have negatively charged cell surface polyanions such as heparin and sialic acid commonly found on host cells (Kazatchkine et al. 1979, Meri & Pangburn 1990). This mediates protection of plasma-exposed host structures.
			R-HSA-166721 (Reactome)	The MBL polypeptide chain consists of a short N-terminal cysteine-rich region, a collagen-like region comprising 19 Gly-X-Y triplets, a 34-residue hydrophobic stretch, and a C-terminal C-type lectin domain. MBL monomers associate via their cysteine-rich and collagen-like regions to form homotrimers, and these in turn associate into oligomers. The predominant oligomers found in human serum contain three (MBL-I) or four (MBL-II) homotrimers (Fujita et al. 2004; Teillet et al. 2005). Extracellular MBL oligomers circulate in plasma in complexes with MASP1/2. The carbohydrate recognition domain (CRD) of MBL binds carbohydrates with 3- and 4- OH groups in the pyranose ring, such as mannose and N-acetyl-D-glucosamine, in the presence of Ca2+. Such motifs occur on the surfaces of viruses, bacteria, fungi and protozoa. The affinity of any one MBL binding site for a carbohydrate ligand is low, but interaction between multiple binding sites on an MBL oligomer and a repetitive carbohydrate motif on a target surface allow high-avidity binding. The specificity of the MBL binding site (it does not bind glucose or sialic acid) and the requirement for a repeated target motif may account for the failure of MBL to bind human glycoproteins under normal conditions (Petersen et al. 2001). This reaction in particular represents the interaction of MBL with bacterial mannose repeats.
			R-HSA-166726 (Reactome)	MBL or ficolins binding to carbohydrates on the target surface results in conformational changes in the lectin:MASPs complex. It in turn promotes a cleavage of proenzyme form of MASP between the CCP2 and the serine protease domains, which results in the generation of the active form. The active form of MASP-2 is able to cleave C4 and C2 to generate the C3 convertase (Vorup-Jensen T et al. 2000; Chen CB and Wallis R 2004). The active form of MASP-1 was shown to facilitate the complement activation by either direct cleavage of complex-bound MASP-2 or cleavage of C2 bound to C4 (Matsushita M et al. 2000; Heja D et al. 2012).
			R-HSA-166753 (Reactome)	The alpha chain of C4 is cleaved, releasing an N-terminal portion of this chain as C4a. The beta and gamma chains are not cleaved and remain linked to the alpha chain by disulfide bonds (Nagasawa et al. 1976, 1980). The resulting C4b heterotrimer undergoes a gross conformational change; the internal thioester in C4b becomes exposed and able to form covalent bonds with surrounding molecules (Law and Dodds 1997). A large proportion of the bonds formed are with water, but some will attach C4b to biological surfaces (Rother et al. 1998). This irreversible reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Fujita et al. 2004; Hajela et al. 2002), and by activated C1, generated through the classical pathway (Muller-Eberhard and Lepow 1965). N.B. Humans have two highly polymorphic loci for Complement factor 4, C4A and C4B. C4A alleles carry the Rodgers (Rg) blood group antigens while the C4B alleles carry the Chido (Ch) blood group antigens. The two loci encode non identical C4 peptides; C4 derived from C4A reacts more rapidly with the amino groups of peptide antigens while C4B allotypes react more rapidly with the hydroxyl group of carbohydrate antigens. The names of the two loci are always represented in uppercase. C4a and C4b refer to the peptide products of Complement Factor 4 cleavage.
			R-HSA-166792 (Reactome)	C2 is cleaved into the large C2a and the small C2b fragment. This irreversible, extracellular reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Vorup-Jensen et al. 2000), and by activated C1, generated through the classical pathway (Nasagawa and Stroud 1977). N.B. Early literature refers to the larger fragment of C2 as C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. For this reason recent literature may refer to the larger C2 fragment as C2b, and the classical C3 convertase as C4bC2b. Throughout this pathway, Reactome uses the current (Feb 2012) Uniprot names which adhere to the original naming practice.
			R-HSA-166795 (Reactome)	C4b and C2a form a complex termed the classical pathway C3 convertase (Muller-Eberhard et al. 1967). C2a that fails to bind C4b is rapidly inactivated.
			R-HSA-166817 (Reactome)	C4b and C2a bind to form the classical pathway C3-convertase (C4bC2a), C3b and the Bb fragment of Factor B form the alternative pathway C3 convertase (C3bBb). The C3(H2O):Bb C3 convertase is sometimes called the initiating convertase, and the C5 convertases also have C3 convertase activity (Rawal & Pangburn 2001). All three pathways merge at the proteolytic cleavage of component C3 by C3 convertases to form two fragments C3b and C3a. The cleavage of component C3 exposes a reactive thioester bond on C3b, leading to the covalent attachment of C3b to glycoproteins on the target cell surface (Law SK et al. 1979; Tack BF et al. 1980). The opsonization with C3b enables the recruitment of phagocytes (Newman SL et al. 1985; Gadjeva M et al. 1998). In addition, C3b anchors the assembly of C3/C5 convertases leading to an amplification of C3 cleavage and effecting C5 activation (Fearon DT 1979; Takata Y et al 1987; Kinoshita T et al. 1988). Moreover, the activation of C3b exposes binding sites for factors B, H and I, properdin, decay accelerating factor (DAF), membrane cofactor protein (MCP), complement receptor 1 (CR1) and microbial molecules such as vaccinia virus complement-control protein and staphylococcal complement inhibitor (SCIN) from Staphylococcus aureus (Forneris F et al. 2010; Morgan HP et al. 2011; Nilsson SC et al. 2010; Lambris JD et al. 1984; Medof ME et al.1984; Barilla-LaBarca ML et al. 2002; Smith BO et al. 2002; Bernet J et al. 2004; Garcia Bl et al. 2010) . C3b associates with these molecules to mediate the activation, amplification and regulation of the complement response.
			R-HSA-173626 (Reactome)	C1 activation requires interaction with two separate Fc domains, so pentavalent IgM antibody is far more efficient at complement activation than IgG antibody (Muller-Eberhard and Kunkel 1961). Antibody binding results in a conformational change in the C1r component of the C1 complex and a proteolytic cleavage of C1r, activating it (Ziccardi and Cooper 1976). This reaction is irreversible under physiological conditions.
			R-HSA-173631 (Reactome)	In this irreversible reaction, the activated C1r subunit of the C1:antibody:antigen complex cleaves the C1s subunit of the complex, activating it in turn (Ziccardi and Cooper 1976). The resulting complex is a C4 activator.
			R-HSA-173636 (Reactome)	C5 convertases are serine proteases that cleave C5 with high efficiency; the C3 convertases can cleave C5 but have a poor affinity for C5, with a Km of 6-9 microM. The high affinity C5 convertases are generated when the low affinity C3/C5 convertases such as C4b:C2a deposit C3b by cleaving native C3. These C3b-containing C3/C5 convertases have Km values of 0.005 microM, well below the normal concentration of C5 in blood (0.37 microM). They have very low Vmax rates, just one C5 cleaved per 1â€“4 min per enzyme (Rawal & Pangburn 1998).
			R-HSA-173680 (Reactome)	Cleavage of C5 by C5 convertases is the last enzymatic step in the complement activation. C5 convertases are formed when C3b molecule is covalently deposited in the immediate vicinity of pre-assembled C3 convertases switching them to C5 convertases C4bC2aC3b and C3bBbC3b (Takata Y et al 1987; Kinoshita T et al. 1988; Rawal N and Pangburn MK 2001, 2003). The additional C3b acts like an anvil for C5; it interacts with C5 and presents C5 in the correct conformation for cleavage by the C2a or Bb enzyme. The proteolytic cleavage of C5 generates the small fragment C5a and the large fragment C5b. C5b initiates an assembly of terminal complement components (C6-C9) leading to the formation of membrane attack complex (MAC) on the target surface (Aleshin AE et al. 2012; Hadders MA et al. 2012). MAC disrupts the cell membrane causing a subsequent cell death through osmotic lysis. Anaphylatoxin C5a mediates pro-inflammatory and immunemodulatory signals via its receptors C5aR and C5L2. The anaphylatoxin receptors are found on surfaces of phagocytes as well as other cell types. In inflammation, they induce cytokine production, degranulation and chemotaxis of leukocytes (Monk PN et al. 2007).
			R-HSA-173705 (Reactome)
			R-HSA-173709 (Reactome)
			R-HSA-173720 (Reactome)
			R-HSA-173723 (Reactome)
			R-HSA-173725 (Reactome)	The membrane attack complex is composed of one C5:C6:C7:C8 complex and between 12-15 C9 molecules (Podack et al. 1982 - 12 represented in this reaction).
			R-HSA-173739 (Reactome)	The thioester linkage between cysteine residue 1010 and glutamine residue 1013 in the alpha chain of Complement factor 3 (C3) can spontaneously hydrolyze, yielding so-called C3(H2O) (Tack et al. 1980; Pangburn & Muller-Eberhard 1980; Pangburn et al. 1981). Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B. The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn & Muller-Eberhard 1983). If not bound by Factor B, C3(H2O) binds Factor H and is inactivated by Factor I
			R-HSA-173740 (Reactome)	Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B (Schreiber et al. 1978). The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn & Muller-Eberhard 1983).
			R-HSA-173745 (Reactome)	Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the soluble C3(H2O):Factor B complex, yielding C3(H2O):Factor Bb and an inactive polypeptide, Factor Ba (Fearon and Austin 1975; Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978).
			R-HSA-173754 (Reactome)	C3b:Bb is naturally labile with a half-life of ~90 s; association of the complex with properdin extends the half-life to ~30 min. (Medicus et al. 1976). Properdin is found in the blood as a mixture of multivalent oligomers: 30% dimers, 45% trimers, 10% tetramers, and 15% higher oligomers. Monomers associate with one another in a head-to-tail arrangement, producing closed circular structures (Smith et al. 1984; Alcorlo M et al. 2013). These features suggest that the properdin oligomer associated with a C3b:Bb complex on a surface such as a cell membrane can facilitate recruitment of additional C3b:Bb complexes to the site (Farries et al. 1988; Hourcade 2006).
			R-HSA-174551 (Reactome)	The complex of C3b:Factor Bb, stabilized on the cell surface by properdin, catalyzes the cleavage of C3 to yield C3b and C3a. The C3b is recruited to the C3b:Factor B complex through its interaction with properdin (Daha et al. 1976; Medicus et al. 1976; Hourcade 2006), yielding the alternate C5 convertase.
			R-HSA-183122 (Reactome)	Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the cell surface-associated C3b:Factor B complex, yielding the alternate C3 convertase C3bBb on the surface and releasing an inactive polypeptide, Factor Ba (Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978).
			R-HSA-183126 (Reactome)	C3b on a surface binds Factor B from solution to form a complex (Schreiber et al. 1978; Muller-Eberhard 1988).
			R-HSA-183130 (Reactome)	C3(H2O):Factor Bb is a C3 convertase, sometimes referred to as the initial C3 convertase (iC3). The Factor Bb component catalyzes the hydrolysis of C3 to produce C3b and C3a. This reaction is not known to be directly coupled to the association of C3b complexes with a cell surface. It is believed that a small proportion of C3b spontaneously associates with the cell surface, otherwise it is rapidly inactivated (Muller-Eberhard 1988).
			R-HSA-2530429 (Reactome)	Complement proteins C8 and C9 can bind to VTN:C5b:C6:C7 to form soluble C5b-C9 complex in plasma. The vitronectin binding to C5b-C9 complex prevents C9 polymerization by rendering it water-soluble and lytic inactive.
			R-HSA-2530445 (Reactome)	CD59, the major inhibitor of the complement membrane attack complex, is an 18–20 kDa glycoprotein, linked to the membrane via a glycosylphosphatidylinositol (GPI)-anchor. It interacts with complement components C8 and C9 during assembly of the membrane attack complex (MAC) and inhibits C9 polymerization, thus preventing the formation of MAC [Lehto T and Meri S. 1993;Rollins SA et al 1991]
			R-HSA-2530453 (Reactome)	Vitronectin interacts with C5b:C6:C7 complex preventing it from the binding with the cell membrane
			R-HSA-2855047 (Reactome)	Cleavage of C4 exposes a highly reactive thioester bond on the C4b molecule. The thioester bond is rapidly inactivated by hydrolysis if C4b does not bind to the target cell surface [Sepp A et al 1993].
			R-HSA-2855054 (Reactome)	Human ficolin-2 (L-ficolin, P35 or FCN2) is synthesised in the liver and secreted into the bloodstream where it recognizes various capsulated bacteria and exhibits binding specificity for diverse ligands, such as lipoteichoic acid, 1,3-beta-d-glucan, and acetylated compounds [Lynch NJ et al. 2004; Aoyagi Y et al. 2008; Ma YG et al. 2004; Garlatti V et al. 2007; Gout E et al 2010]. Ficolin-2 also binds to apoptotic HL60, U937, and Jurkat cells [Kuraya M, et al. 2005].
			R-HSA-2855077 (Reactome)	Ficolin-3 (H-ficolin, FCN3 or Hakata antigen) activates the lectin pathway of complement similar to mannose-binding lectin. Ficolin-3 is composed by a collagen-like strand and three C-terminal recognition domains which bind to carbohydrates on the target surface. Ficolin-3 circulates in plasma associated with mannan-binding lectin-associated serine proteases (MASPs). Upon ligand binding ficolin-3:MASPs complex triggers activation of the lectin pathway [Matsushita M et al. 2002; Teillet F et al. 2008; Zacho RM et al. 2012]. Ficolin-3 (FCN3 or H-ficolin) can specifically recognize Aerococcus viridans [Tsujimura M et al. 2002; Zacho RM et al. 2012]. Ficolin-3 has been shown to bind to patterns of bacterial polysaccharides such as d-fucose and galactose [Garlatti V et al. 2007]. In adition to pathogenic ligands ficolin-3 was reported to bind to apoptotic Jurkat cells [Kuraya M et al. 2005].
			R-HSA-2855125 (Reactome)	Ficolin-1 (M-ficolin or FCN1) was shown to localize at the cell surface of circulating monocytes and granulocytes, despite lacking an obvious transmembrane domain, (Teh C et al. 2000; Honore C et al. 2010). Ficolin-1 has also been found in human plasma (Honore C et al. 2008; Wittenborn T et al. 2010; Kjaer TR et al. 2011). Monocytes and macrophages, but not immature dendritic cells were reported to secrete Ficolin-1 into the serum (Honore C et al. 2010). Moreover, early studies revealed its presence in secretory granules of peripheral blood monocytes and granulocytes (Liu Y et al. 2005). Soluble Ficolin-1 was found to form a complex with MASP2, while cell surface-bound Ficolin-1 did not associate with MASP (Honore C et al. 2010; Kjaer TR et al. 2011). Ficolin-1 specifically recognizes sialic acid and can bind to acetylated compounds such as N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) (Garlatti V et al. 2007; Gout E et al. 2010; Kjaer TR et al. 2011).
			R-HSA-3266557 (Reactome)	Factor I (FI) inactivates C3 convertase activity by cleavage C3b producing iC3b, which remains bound to the membrane. A final proteolytic cleavage converts iC3b into two molecules, C3c, which is released into solution, and C3dg, which remains attached to the membrane. This cleavage requires CR1, which serves as a cofactor for cleavage of iC3b by factor I (Medof ME et al. 1982). iC3b and C3dg are active molecules, that can bind CR2 (CD21) to enhance B-cell immunity (Tuveson DA et al.1991; Sarrias MR et al. 2001).
			R-HSA-976743 (Reactome)	Complement factor I cleaves the alpha chain of C3b at two positions, generating inactivated C3b (iC3b) and a small fragment C3f which is released. The majority of the alpha chain is retained as two fragments which are tethered by disulphide bonds. iC3b is proteolytically inactive.
			R-HSA-976768 (Reactome)	Factor H (FH) regulates the alternative pathway C3 convertase C3bBb and its C3b component both in plasma and at host cell surfaces. FH binds to plasma C3b, making it unavailable, and acts as a cofactor for the factor I-mediated proteolytic inactivation of C3b to iC3b.
			R-HSA-976801 (Reactome)	Complement factor I (CFI) is a complex of one heavy and one light chain, both cleaved from the same precursor peptide. It inactivates complement subcomponents C3b, iC3b and C4b by proteolytic cleavage of the alpha chains of C4b and C3b in the presence of cofactors such as Factor H, C4b binding protein, Complement receptor 1 (CR1) or MCP (CD46).
			R-HSA-976810 (Reactome)	Complement factor I binds the factor H:C3b complex.
			R-HSA-977359 (Reactome)	Complement factor I binds to the Factor H:C3b complex.
			R-HSA-977363 (Reactome)	Factor H (FH) binds to C3bBb, leading to displacement of Bb. Complement factor H-related protein 3 (FHR-3) has also been reported to bind C3Bb leading to inhibition of C3Bb C3 convertase activity (Fritsche et al. 2010). FH also acts as a cofactor for the factor I-mediated proteolytic inactivation of C3b to iC3b.
			R-HSA-977371 (Reactome)	Following the displacement of Bb from C3bBb, Factor I cleaves Factor H-bound C3b producing iC3b, which remains bound to the membrane. The majority of the C3b alpha chain is retained as two fragments which are tethered to the beta chain by disulphide bonds. iC3b is proteolytically inactive and cannot contribute to the complement cascade process, though it still contributes to opsonization.
			R-HSA-977375 (Reactome)	Complement Receptor 1 (CR1) is a widely distributed cell surface protein that is a decay accelerating factor for the conventional (C4bC2a) and alternative (C3bBb) C3 convertases (Coico & Sunshine 2009).
			R-HSA-977602 (Reactome)	Membrane cofactor protein (MCP) and Complement Receptor 1 (CR1) act as cofactors for the protease activity of complement factor I which binds MCP or CR1 complexes with C3b or C4b, inactivating C3b/C4b.
			R-HSA-977605 (Reactome)	Factor H greatly accelerates the displacement (decay) of Complement factor Bb from C3b.
			R-HSA-977615 (Reactome)	Factor I cleaves the truncated alpha (a') chain of C4b between Arg-1336 and Asn-1337 and then again between Arg-956 and Thr-957, producing a 16 kDa fragment known as alpha4, derived from the C terminus of the a' chain, followed by a 27 kDa alpha3 fragment. The remaining alpha 2 (C4d) fragment stays covalently bound to the cell membrane while the complex of disulfide-linked alpha3, alpha4, beta chain and gamma chain are released (C4c) into the fluid phase (Fujita et al. 1978).
			R-HSA-977619 (Reactome)	Decay accelerating factor (DAF, CD55) is a widely distributed membrane protein. It accelerates the dissociation of C3bBb and C4C2a, thereby inhibiting the amplification of complement. DAF can bind C3b and Bb but must bind both for efficient decay acceleration. The regulatory function of DAF is believed to be inhibition of activated C3 convertase enzymes rather than binding of inactive proenzymes (Harris et al. 2007).
			R-HSA-977626 (Reactome)	The most abundant form of C4b-binding protein (C4BP) consists of seven alpha-chains (70kDa) and one beta-chain (45kDa) all linked by disulphide bonds to form a native protein with a molecular weight of 570kDa (Hilarp et al. 1989). Each alpha chain can bind C4b; it is not known whether full occupancy is necessary for subsequent events. The beta chain binds and inactivates Protein S, a component of the coagulation system. C4BP down-regulates complement activity in several ways: It binds to C4b thus inhibiting the formation of the classical pathway C3 convertase C4bC2a; it acts as a decay accelerating factor for existing convertases, probably by promoting dissociation of C2a; it is a cofactor in Factor I mediated C4b proteolysis.
			R-HSA-977629 (Reactome)	Complement Receptor 1 (CR1) displaces the activated enzyme components Bb and C2a from the conventional and alternative C3 convertases C4bC2a and C3bBb, respectivley.
			R-HSA-981535 (Reactome)	Decay-accelerating-factor (DAF, CD55) is a membrane- bound complement regulatory protein that inhibits autologous complement cascade activation. It is expressed on all cells that are in close contact with serum complement proteins, but also on cells outside the vascular space and on tumour cells. DAF binds to C3bBb and C4bC2a on cell surfaces, accelerating their dissociation and thereby inhibiting the amplification of complement. DAF can bind C3b and Bb, and must bind both for efficient decay acceleration. Although it can bind the inactive proenzymes C3b and C4b, the regulatory function of DAF is believed to be inhibition of activated C3 convertase enzymes (Harris et al. 2007).
			R-HSA-981539 (Reactome)	Metastable C3b can bind a wide variety of proteins and carbohydrates expressed on biological surfaces (Coico & Sunshine, 2009; Kimball 2010). This is an essentially random event (Dodds & Law, 1998); binding may be to host or microorganism. However, certain surface sugars have greater C3b binding rates, perhaps explaining variations in microorganism suceptibility (Pangburn, M. in The Complement System, Ed. Rother et al. 1998).
			R-HSA-981621 (Reactome)	C3b:Bb is naturally labile with a half-life of ~90 s. unless bound to properdin on the cell surface (Medicus et al. 1976). C4bC2a is also unstable, lasting at best a few minutes (Kerr et al. 1980). Decay is associated with the release of the Bb or C2a fragments respectively into the fluid phase. The liberated C3b/C4b is able to re-bind Bb/C2a if Factor B/C2 are present.
			R-HSA-981637 (Reactome)	C4b-binding protein is a cofactor in Factor I mediated C4b proteolysis. C4b is cleaved, releasing C4c, leaving C4d bound to the cell surface.
			R-HSA-981648 (Reactome)	C4 binding protein accelerates the decay of C4bC2a in a dose-dependent fashion, without causing degradation of C4b, and is presumed to bind to the convertase to mediate this effect.
			R-HSA-981658 (Reactome)	C4b-binding protein is a cofactor for Complement Factor I, allowing it to bind and thereby mediating C4b proteolysis.
			R-HSA-981665 (Reactome)	The beta subunit of C4b binding protein binds and inactivates Protein S, a vitamin K dependent anticoagulation factor. This may represent part of a mechanism for fine-tuning the process of phagocytosis (Kask et al. 2004).
			R-HSA-981680 (Reactome)	C4 binding protein accelerates the decay of C4bC2a in a dose-dependent fashion. The mechanism of this is poorly understood, but is distinct from Factor I mediated degradation of C4b and believed to represent the displacement of C2a from specific binding sites on C4b (Gigli et al. 1979).
			R-HSA-981713 (Reactome)	The cleavage of C4 into C4a and C4b releases an acyl group from the intrachain thioester bond, allowing C4b to bond covalently to any adjacent biological substrates (Dodds & Law 1998). C4 is encoded at two loci, C4A and C4B. The C4b proteins derived from these genes are not identical and have different binding preferences (Law et al 1984, Sepp et al. 1993); C4A-derived C4b binds more efficiently than C4B-derived C4b to amino groups, while C4B-derived C4b is more effective than C4A in binding to hydroxyl groups. The site of C4b deposition is not clearly established (MÃ¸ller-Kristensen et al. 2003) but generally accepted to be the activating cell membrane surface, though it may be the activating complex itself.
			R-HSA-981728 (Reactome)	Factor H (FH) regulates the alternative pathway C3 convertase C3bBb and its C3b component both in plasma and at host cell surfaces. FH binds to membrane-associated C3b, competing with Factor B and thereby preventing formation of the active C3 convertase C3bBb. In addition, it acts as a cofactor for the Factor I-mediated proteolytic inactivation of C3b to iC3b.
	VTN:C5b:C6:C7:C8:C9	Arrow	R-HSA-2530429 (Reactome)
	VTN:C5b:C6:C7	Arrow	R-HSA-2530453 (Reactome)
VTN:C5b:C6:C7			R-HSA-2530429 (Reactome)
VTN			R-HSA-2530453 (Reactome)
	iC3b	Arrow	R-HSA-976743 (Reactome)
	iC3b	Arrow	R-HSA-977371 (Reactome)
	thioester-C1010-Q1013-C4b	Arrow	R-HSA-166753 (Reactome)
thioester-C1010-Q1013-C4b			R-HSA-2855047 (Reactome)
thioester-C1010-Q1013-C4b			R-HSA-977626 (Reactome)
thioester-C1010-Q1013-C4b			R-HSA-981713 (Reactome)

Complement cascade (Homo sapiens)

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