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Information on EC 3.4.21.43 - classical-complement-pathway C3/C5 convertase and Organism(s) Homo sapiens
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3.4.21.43 classical-complement-pathway C3/C5 convertaseSpecify your search results
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The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Selective cleavage of Arg-/-Ser bond in complement component C3 alpha-chain to form C3a and C3b, and Arg-/- bond in complement component C5 alpha-chain to form C5a and C5b
Synonyms
c3bbbp, c4b2a, classical pathway c3 convertase, classical c3 convertase, c4b,2a, classical pathway c5 convertase, complement c3 convertase, c4bc2a, cp c3 convertase, soluble c3 convertase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
C3 convertase
C3/C5 convertase
C3bBb
C4
-
-
-
-
C423
-
-
-
-
C4b,2a
-
-
-
-
C4b,2a,3b
-
-
-
-
C4b,C2a
C4b2a
C5 convertase
complement C3 convertase
-
-
-
-
C3 convertase
-
-
-
-
C3 convertase
-
-
C3/C5 convertase
-
-
-
-
C5 convertase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
Selective cleavage of Arg-/-Ser bond in complement component C3 alpha-chain to form C3a and C3b, and Arg-/- bond in complement component C5 alpha-chain to form C5a and C5b
hydrolyses peptide bond 77 (Arg-Ser) in complement component C3, and complement component C5. Cleavage of C5 requires complement fragment C3b which binds C5 and renders it susceptible to cleavage by the C4b,C2a complex
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
56626-15-4
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
complement component C3 + H2O
?
-
classical pathway of the complement system
-
-
?
complement component C3 + H2O
component C3b + anaphylatoxin C3a
-
-
iC3b is generated by Factor I after formation of C3b. iC3b is a proteolytically inactive form of C3b that retains the ability to opsonize microbes, but cannot participate in convertase function
-
?
complement component C5 + H2O
?
-
activity of enzyme bound to component C3b
-
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
-
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
-
-
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
hydrolyzes peptide bond Arg77-Ser of the alpha-chain of C3
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
complement component C3 is the preferred substrate. Cleavage of the preferred C3 substrate and deposition of C3b effectively switches the output of the enzyme from C3b to C5b, resulting in initiation of the cytosolic process of complement
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
C3 complement cleavage is a central event in the activation of the complement system via the classical, the alternative, and the lectin pathway, overview
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
-
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
hydrolyzes peptide bond Arg77 of the alpha-chain of complement component C5, cleavage of C5 requires complement fragment C3b which binds C5 and renders it susceptible to cleavage by the C4b,C2a complex
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases C4b2aC3b and C3b 2 Bb
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases, C4b2a3b and C3b2Bb, cleave C5 into the anaphylatoxin C5a and C5b followed by initiation of the terminal pathway, leading to formation of lytic C5b-9 membrane attack complexes, overview
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases, C4b2a3b and C3b2Bb, cleave C5 into the anaphylatoxin C5a and C5b, overview
-
-
?
complement componentC3 + H2O
complement component C3a + complement component C3b
-
C3 convertase C3bBb
-
-
?
complement componentC3 + H2O
complement component C3a + complement component C3b
-
C3 convertases, C4b2a and C3bBb, cleave C3 into the anaphylatoxin C3a and C3b, overview
-
-
?
additional information
?
-
-
dissociation of the classical-complement-pathway C3/C5 convertase by the regulators decay-accelerating factor, DAF, complement receptor 1, CR1, factor H and C4-binding protein C4BP, controls the function of the enzyme. Decay acceleration mediated by DAF, C4BP and CR1 requires interaction of the alpha4/5 region of C2a with a CCP2/CCP3 site of DAF or structurally homologous sites of CR1 and C4BP
-
?
additional information
?
-
-
the enzyme has a very short half-life. Dissociation of the two noncovalently bound subunits proceeds with a half_life of 1-3 min at 37°C under physiological conditions, and this rate increases greatly if regulatory proteins are present. Numerous decay-accelerating proteins are present in plasma and on host cells that bind to the noncatalytic subunit C4b and increase the rate at which the catalytic subunit C2a is released into the medium. C2a loses its enzymatic activity and its ability to bind to C4b upon release. Although C4b is able to rebind C2 and reform the enzyme, the interaction with most decay-accelerating factors also leads to permanent proteolytic interaction of the cell-bound subunit C4b by a fluid-phase protease Factor I. Theses regulatory events limit cleavage of C3, reduce release of the anaphylatoxin C3a and control the formation of more efficient C5 convertase enzymes
-
?
additional information
?
-
-
factor B associates with complement component C3b and after proteolysis yields the C3 convertase of the alternative pathway, complement component C2A provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation, structural basis of the substrate specificity of the complement complex, overview, attachment of C3b to either C4b2a or C3bBb yields the C5 convertases, C4b2a3b and C3b2Bb, respectively, that cleave complement component C5
-
-
?
additional information
?
-
-
the alternative pathway lead via C3 convertase C3bBb and the C5 convertases C4b2aC3b and C3b 2 Bb
-
-
?
additional information
?
-
-
the C3 convertases, bimolecular complexes C4b2a and C3bBb, of the classical and alternative pathways are the central enzymes of the complement cascade, focused complement activation on foreign targets depends on regulatory proteins that decay the bimolecular C3 convertases, activity and regulation of complement control proteins CCP1-CCP4 as modules of the cell surface regulator, decay-accelerating factor, i.e. DAF or CD55, interaction of DAF with the convertases is mediated predominantly by two patches, one centered around Arg69 and Arg96 on CCP2 and the other around Phe148 and Leu171 on CCP3, structure, overview
-
-
?
additional information
?
-
-
the multi-domain serine protease C2 is the catalytic fragment of classical pathway C3 and C5 convertase of human complement of the classical and lectin pathways of complement activation, formation of these convertases requires the Mg2+-dependent binding of C2 to C4b and the subsequent cleavage of C2 by C1s or MASP2, respectively, the C-terminal fragment C2a consisting of a serine protease and a von Willebrand factor type A domain, remains attached to C4b, forming the C3 convertase, C4b2a, structure, overview
-
-
?
additional information
?
-
-
the virion-associated Kaposis sarcoma-associated herpesvirus complement control protein is required for complement regulation and cell binding, involved structures, Kaposis sarcoma-associated herpesvirus, KSHV, encodes a lytic cycle protein called KSHV complement control protein, KCP, that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases, KCP is expressed on the surface of human infected endothelial cells, mechanism, overview, K64Q/K65Q/K88Q KCP mutant lacks complement regulatory activity
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
complement component C3 + H2O
?
-
classical pathway of the complement system
-
-
?
complement component C3 + H2O
component C3b + anaphylatoxin C3a
-
-
iC3b is generated by Factor I after formation of C3b. iC3b is a proteolytically inactive form of C3b that retains the ability to opsonize microbes, but cannot participate in convertase function
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
-
-
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
complement component C3 is the preferred substrate. Cleavage of the preferred C3 substrate and deposition of C3b effectively switches the output of the enzyme from C3b to C5b, resulting in initiation of the cytosolic process of complement
-
?
complement component C3 + H2O
complement component C3a + complement component C3b
-
C3 complement cleavage is a central event in the activation of the complement system via the classical, the alternative, and the lectin pathway, overview
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
-
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases C4b2aC3b and C3b 2 Bb
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases, C4b2a3b and C3b2Bb, cleave C5 into the anaphylatoxin C5a and C5b followed by initiation of the terminal pathway, leading to formation of lytic C5b-9 membrane attack complexes, overview
-
-
?
complement component C5 + H2O
complement component C5a + complement component C5b
-
C5 convertases, C4b2a3b and C3b2Bb, cleave C5 into the anaphylatoxin C5a and C5b, overview
-
-
?
complement componentC3 + H2O
complement component C3a + complement component C3b
-
C3 convertase C3bBb
-
-
?
complement componentC3 + H2O
complement component C3a + complement component C3b
-
C3 convertases, C4b2a and C3bBb, cleave C3 into the anaphylatoxin C3a and C3b, overview
-
-
?
additional information
?
-
-
dissociation of the classical-complement-pathway C3/C5 convertase by the regulators decay-accelerating factor, DAF, complement receptor 1, CR1, factor H and C4-binding protein C4BP, controls the function of the enzyme. Decay acceleration mediated by DAF, C4BP and CR1 requires interaction of the alpha4/5 region of C2a with a CCP2/CCP3 site of DAF or structurally homologous sites of CR1 and C4BP
-
?
additional information
?
-
-
the enzyme has a very short half-life. Dissociation of the two noncovalently bound subunits proceeds with a half_life of 1-3 min at 37°C under physiological conditions, and this rate increases greatly if regulatory proteins are present. Numerous decay-accelerating proteins are present in plasma and on host cells that bind to the noncatalytic subunit C4b and increase the rate at which the catalytic subunit C2a is released into the medium. C2a loses its enzymatic activity and its ability to bind to C4b upon release. Although C4b is able to rebind C2 and reform the enzyme, the interaction with most decay-accelerating factors also leads to permanent proteolytic interaction of the cell-bound subunit C4b by a fluid-phase protease Factor I. Theses regulatory events limit cleavage of C3, reduce release of the anaphylatoxin C3a and control the formation of more efficient C5 convertase enzymes
-
?
additional information
?
-
-
factor B associates with complement component C3b and after proteolysis yields the C3 convertase of the alternative pathway, complement component C2A provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation, structural basis of the substrate specificity of the complement complex, overview, attachment of C3b to either C4b2a or C3bBb yields the C5 convertases, C4b2a3b and C3b2Bb, respectively, that cleave complement component C5
-
-
?
additional information
?
-
-
the alternative pathway lead via C3 convertase C3bBb and the C5 convertases C4b2aC3b and C3b 2 Bb
-
-
?
additional information
?
-
-
the C3 convertases, bimolecular complexes C4b2a and C3bBb, of the classical and alternative pathways are the central enzymes of the complement cascade, focused complement activation on foreign targets depends on regulatory proteins that decay the bimolecular C3 convertases, activity and regulation of complement control proteins CCP1-CCP4 as modules of the cell surface regulator, decay-accelerating factor, i.e. DAF or CD55, interaction of DAF with the convertases is mediated predominantly by two patches, one centered around Arg69 and Arg96 on CCP2 and the other around Phe148 and Leu171 on CCP3, structure, overview
-
-
?
additional information
?
-
-
the multi-domain serine protease C2 is the catalytic fragment of classical pathway C3 and C5 convertase of human complement of the classical and lectin pathways of complement activation, formation of these convertases requires the Mg2+-dependent binding of C2 to C4b and the subsequent cleavage of C2 by C1s or MASP2, respectively, the C-terminal fragment C2a consisting of a serine protease and a von Willebrand factor type A domain, remains attached to C4b, forming the C3 convertase, C4b2a, structure, overview
-
-
?
additional information
?
-
-
the virion-associated Kaposis sarcoma-associated herpesvirus complement control protein is required for complement regulation and cell binding, involved structures, Kaposis sarcoma-associated herpesvirus, KSHV, encodes a lytic cycle protein called KSHV complement control protein, KCP, that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases, KCP is expressed on the surface of human infected endothelial cells, mechanism, overview, K64Q/K65Q/K88Q KCP mutant lacks complement regulatory activity
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
CN-
-
inhibits the aggregation of C4b and C2a and the activity of the active enzyme
complement receptor of immunoglobulin family
-
inhibits C5 conversion specifically
-
eculizumab
-
potently inhibits C5 conversion but leaves C3 conversion unaffected
-
extracellular complement binding protein
-
does not inhibit C3 convertase activity but C5 convertase activity
-
extracellular complement-binding protein
-
Ecb, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, Efb-C and Ecb act on the bacterial surface, overview
-
extracellular fibrinogen-binding protein
-
Efb, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, Efb-C and Ecb act on the bacterial surface, overview
-
factor H related-protein 5
-
inhibits C5 conversion in a concentration-dependent manner
-
hepatitis virus C
-
inhibition of C3 convertase activity and C3b deposition onto bacterial membrane by hepatitis C virus, impairment of both C3 convertase and Factor I activity
-
N-terminal long homologous repeat A of complement receptor type 1
-
responsible for dissociation of enzyme. Highest decay accelerating activity for mutant dimeric construct N-terminal long homologous repeat A (D109N/E116K)/N-terminal long homologous repeat A (D109N)
-
NH2-CD59-DAF-GPI
-
chimeric molecule, DAF: decay accelerating factor, GPI: glycosylphosphatidylinositol
-
NH2DAF-CD59-GPI
-
chimeric molecule, DAF: decay accelerating factor, GPI: glycosylphosphatidylinositol
-
OmCI
-
the inhibitor blocks C5 cleavage by interfering with convertase recognition far from C5a
-
Ornithodoros moubata complement inhibitory protein
-
potently inhibits C5 conversion but leaves C3 conversion unaffected
-
Pra1
-
i. e. Candida albicans complement regulator acquiring surface protein 2 or pH-regulated Ag 1. In the direct surrounding of the pathogen, inhibitor binds to fluid-phase C3, blocks cleavage of C3 to C3a and C3b and inhibits complement activation via the alternative and classical pathways. In addition, the release of the anaphylatoxins C3a and C5a, as well as C3b/iC3b surface deposition, is reduced. By reducing C3b/iC3b levels at the yeast surface, Pra1 decreases complement-mediated adhesion, as well as uptake of Candida albicans by human macrophages
-
SSL7
-
the inhibitor blocks C5 cleavage by interfering with convertase recognition far from C5a
-
staphylococcal complement inhibitor
-
SCIN, a potent complement inhibitor from Staphylococcus aureus, with strong antiinflammatory properties, inhibitory mechanism for blocking C3b-containing convertases, overview
-
thioredoxin 1
-
Trx-1, but not an active site mutated form, inhibits both C3 and C5 classical convertase formation, mechanism, overview. Trx-1 is capable of inhibiting all classical and alternative convertases but its effect is more pronounced in inhibition of alternative ones
additional information
-
Kaposi's sarcoma-associated herpesvirus complement control protein inhibits complement through decay-accelerating activity of the classical C3 convertase and cofactor activity for factor I-mediated degradtion of C4b and C3b, as well as acting as an attachment factor for binding to heparan sulfate on permissive cells, overview
-
additional information
-
the C3b-specific antibody fragment S77 does not inhibit the classical pathway C5 convertase in human serum
-
additional information
-
addition of guinea pig serum in 40 mM EDTA initiates lysis of existing convertase complexes and excludes the possibility of de novo convertase formation
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
C3b
-
both the soluble form of the enzyme, C4b,C2a and the surface-bound form of the enzyme EAC1,C4b,C2a exhibit a poor affinity for the substrate C5. Very high affinity C5 convertase is generated only when the low affinity C3/C5 convertases are allowed to deposit C3b by cleaving native C3
-
complement component C3b
-
in inactive surface-fixed form essential for cleavage of C5
-
factor B
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
factor D
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
properdin
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
-
zymosan
-
it is capable of activating the classical pathway as well as the alternative pathway, when the classical pathway is blocked, mechanism, overview
-
additional information
-
cooperation of the enzyme with MBL-associated serine proteases MASP-1 and MASP-2 in C3 cleavage, the serine proteases generate active C3 convertase at high serum concentration, while MASP-3 inhibits it, overview
-
additional information
-
properdin can initiate complement activation by binding specific target surfaces, e.g. microbial targets like Neisseria gonorrhoeae, and Escherichia coli and Salmonella typhimurium lipopolysaccharide mutants, or yeast cell walls, , and providing a platform for de novo convertase assembly and function via the alternative pathway, overview, recombinant human compound
-
additional information
-
complement activation via the lectin pathway on zymosan particles is at least 4times more efficient than via the classical pathway on sheep erythrocytes coated with antibody. Every C4b deposited via the lectin pathway is capable of forming a convertase in contrast to only one of four C4b molecules deposited via the classical pathway. Rate of formation of lectin pathway C3/C5 convertases depends on the activation of C4 and C2 by MASP-2
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0000011 - 0.0000083
complement component C5
-
37°C, high-affinity C5 convertase EAC1,C3bC4b,C2a
-
0.0000051
complement component C5
-
high affinity C5 convertase (EAC1,C3bC4b,C2a)
-
0.0046 - 0.0066
complement component C5
-
37°C, surface bound C3/C5 convertase, EAC1,C4b,C2a
-
0.0089
complement component C5
-
37°C, soluble monomeric C3/C5 convertase C4b,C2a
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.015 - 0.026
complement component C5
-
37°C, high-affinity C5 convertase EAC1,C3bC4b,C2a
-
0.022
complement component C5
-
37°C, soluble monomeric C3/C5 convertase C4b,C2a
-
0.023 - 0.047
complement component C5
-
37°C, surface bound C3/C5 convertase, EAC1,C4b,C2a
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00025
soluble complement receptor type 1
Homo sapiens
-
at 37°C, pH not specified in the publication
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
81407, 81408, 81410, 81411, 81412, 81413, 81414, 81415, 649815, 652460, 652494, 653251, 669726, 680169, 683532, 683646, 683716, 683737, 683775, 683831, 684068, 695326, 698871, 709002, 710434
-
-
2 distinct C3 convertases generated by 2 seperate enzyme cascade systems
-
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
inhibition of C3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components. Inhibition of C3 convertase activity and C3b deposition onto bacterial membrane by hepatitis C virus, impairment of both C3 convertase and Factor I activity, overview
metabolism
physiological function
additional information
-
the classical C5 convertase requires factor D, factor B, and properdin for activation and complex assembly
metabolism
-
all pathways converge at the level of the C3 molecule, where downstream events can be amplified by a mechanism of positive feedback supported by complement convertases: the classical/lectin pathway C3 convertase (C4b2a) or the alternative pathway C3 convertase (C3bBb). These convertases further cleave C3 to C3b and C3a, of which C3b binds to nearby surfaces, providing a convertase assembly platform, or to pre-assembled C3 convertases, switching them to C5 convertases (C4b2aC3b or C3bBbC3b, respectively). The C5 convertase cleaves C5 molecules to C5a and C5b and the latter initiates formation of the membrane attack complex (MAC, C5b678polyC9) and its insertion into a target membrane. Enzyme regulation, overview
metabolism
-
further processing of enzyme reaction product C3b results in the formation of iC3b and C3f, and finally C3c and C3dg
physiological function
-
soluble recognition molecule PTX3, i.e. long pentraxin 3, displays multiple functions including innate immune defense against certain microbes and the clearance of apoptotic cells. In addition to complement activators, PTX3 interacts with complement inhibitors including C4BP. This balanced interaction on extracellular matrix and on apoptotic cells may prevent excessive local complement activation that would otherwise lead to inflammation and host tissue damage. PTX3 binds to the classical and lectin pathway regulator C4b-binding protein C4BP. A PTX3-binding site lies within short consensus repeats 1-3 of the C4BP a-chain. PTX3 does not interfere with the cofactor activity of C4BP in the fluid phase and C4BP maintains its complement regulatory activity when bound to PTX3 on surfaces. PTX3 binds to human fibroblast- and endothelial cell-derived extracellular matrices and recruits functionally active C4BP to these surfaces. Whereas PTX3 enhances the activation of the classical/lectin pathway and causes enhanced C3 deposition on extracellular matrix, deposition of terminal pathway components and the generation of the inflammatory mediator C5a are not increased. PTX3 enhances the binding of C4BP to late apoptotic cells, which resultes in an increased rate of inactivation of cell surface bound C4b and a reduction in the deposition of C5b-9
physiological function
-
modulation of the upstream proteins involved in proteolytic processing of the complement cascade prior to convertase formation is critical in promoting the function of the complement system in response to infection
physiological function
-
zymosan activates the classical pathway by an antigen-antibody reaction in normal human serum requiring IgG and IgM antibodies, it cannot initiate classical pathway activation without the antibodies, regulation, overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). CO2_HUMAN
752
0
83268
Swiss-Prot
Secretory Pathway (Reliability: 1)
A0A0G2JL69_HUMAN
723
0
80150
TrEMBL
Mitochondrion (Reliability: 4)
B4DV48_HUMAN
723
0
80106
TrEMBL
Mitochondrion (Reliability: 4)
Q95IG1_HUMAN
577
0
63458
TrEMBL
Secretory Pathway (Reliability: 1)
H0Y3H6_HUMAN
526
0
58900
TrEMBL
Secretory Pathway (Reliability: 3)
Q53GZ8_HUMAN
752
0
83337
TrEMBL
Secretory Pathway (Reliability: 1)
A0A0G2JIE7_HUMAN
525
0
58789
TrEMBL
Secretory Pathway (Reliability: 4)
Q53HP3_HUMAN
752
0
83284
TrEMBL
Secretory Pathway (Reliability: 1)
Q5JP69_HUMAN
752
0
83268
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1U9X8W4_HUMAN
752
0
83328
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1U9X8X9_HUMAN
752
0
83240
TrEMBL
Secretory Pathway (Reliability: 1)
A0A1U9X8X3_HUMAN
752
0
83254
TrEMBL
Secretory Pathway (Reliability: 1)
CO5_HUMAN
1676
0
188305
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
198000
-
C4bC2a, 1 * 198000 + 1 * 74000, C2a is the catalytic subunit, but unable to catalyze the reaction alone
74000
-
C4bC2a, 1 * 198000 + 1 * 74000, C2a is the catalytic subunit, but unable to catalyze the reaction alone
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
dimer
additional information
dimer
-
C4bC2a, 1 * 198000 + 1 * 74000, C2a is the catalytic subunit, but unable to catalyze the reaction alone
additional information
-
enzyme subunit C3b binds to site 2 of complement receptor type 1
additional information
-
C2 is a glycosylated modular protein consisting of three domains, C2a is the catalytic fragment of classical pathway C3 and C5 convertase of human complement, formation of the convertases requires the Mg2+-dependent binding of C2 to C4b and the subsequent cleavage of C2 by C1s or MASP2, respectively, the C-terminal fragment C2a consisting of a serine protease and a von Willebrand factor type A domain, remains attached to C4b, forming the C3 convertase, C4b2a, three-dimensional structure of the C2a molecule, residues Asp240, Ser242, Ser244, Thr317 and Asp356 constitute the MIDAS motif of C2a, overview
additional information
-
C3 convertase complex structure including complement component C2A and the catalytic triad, crystal structure modeling, overview
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
crystal structures of the C3b homologue cobra venom factor CVF in complex with C5, and in complex with C5 and the inhibitor SSL7, both at 4.3 A resolution. The structures reveal a parallel two-point attachment between C5 and CVF, where the presence of SSL7 only slightly affects the C5-CVF interface, explaining the IgA dependence for SSL7-mediated inhibition of C5 cleavage. CVF functions as a relatively rigid binding scaffold inducing a conformational change in C5, which positions its cleavage site in proximity to the serine protease Bb
Mg2+-bound C2a, hanging drop vapor diffusion method, 22°C, 0.002 ml of 20 mg/ml protein solution is mixed with 0.002 ml of well solution containing 20% w/v polyethylene glycol 10000, 0.1 M HEPES, pH 7.5, and 0.0004 ml of 0.3 M glycyl-glycyl-glycine, 3-7 days, X-ray diffraction structure determination and analysis at 1.9-2.3 A resolution
-
N-terminal segment C2b, by the hanging-drop vapor-diffusion method, to 1.8 A resolution. Space group P31 with unit-cell parameters a=b= 60.09 A and c = 61.69 A. Conformational changes of C2, C2a and C2b during C3 convertase C4bC2a formation
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
C241A
-
C2 mutation, behaves similarly to the wild-type enzyme with slightly elevated hemolytic activity
Q243G
-
C2 mutation reduces C4b2a sensitivity to decay-accelerating factor DAF to 2% of the wild-type, moderately reduces C4b2a sensitivity to complement receptor 1-A to 55% of the wild-type
Y327A
-
C2 mutation reduces C4b2a sensitivity to decay-accelerating factor DAF and to complement receptor 1-A to less than 1% of the wild-type
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
dissociation of the classical-complement-pathway C3/C5 convertase by the regulators decay-accelerating factor, DAF, complement receptor 1, CR1, factor H and C4-binding protein C4BP, controls the function of the enzyme. Decay acceleration mediated by DAF, C4BP and CR1 requires interaction of the alpha4/5 region of C2a with a CCO2/CCO3 site of DAF or structurally homologous sites of CR1 and C4BP
-
in the presence of C4b-binding protein C4BP the assembly of the classical pathway C3-convertase is prevented and its decay is accelerated. Positively charged amino acids at the interface between alpha-chain CCP1 and CCP2 of C4BP are required for regulation of the classical C3-convertase
-
the enzyme has a very short half-life. Dissociation of the two noncovalently bound subunits proceeds with a half-life of 1-3 min at 37°C under physiological conditions, and this rate increases greatly if regulatory proteins are present. Numerous decay-accelerating proteins are present in plasma and on host cells that bind to the noncatalytic subunit C4b and increase the rate at which the catalytic subunit C2a is released into the medium. C2a loses its enzymatic activity and its ability to bind to C4b upon release. Although C4b is able to rebind C2 and reform the enzyme, the interaction with most decay-accelerating factors also leads to permanent proteolytic interaction of the cell-bound subunit C4b by a fluid-phase protease Factor I. Theses regulatory events limit cleavage of C3, reduce release of the anaphylatoxin C3a and control the formation of more efficient C5 convertase enzymes
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
full-length C2 cDNA cloned into the baculovirus expression vector pACgp67A and cotransfected with BD Baculogold Bright linearized baculovirus DNA into sf9 insect cells. High-titer stocks produced in sf9 insect cells and used to infect High Five insect cells for protein expression
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
expression of classical C3 convertase (C4b2a) is decreased in case of hepatitis C viral infection
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
activation of complement via the lectin pathway may be a more prominent contributor to the pathology of inflammatory reactions as compared to activation of complement via the classical pathway
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Nagasawa, S.; Kobayashi, C.; Maki-Suzuki, T.; Yamashita, N.; Koyama, J.
Purification and characterization of the C3 convertase of the classical pathway of human complement system by size exclusion high-performance liquid chromatography
J. Biochem.
97
493-499
1985
Homo sapiens
Kerr, M.A.
The human complement system: assembly of the classical pathway C3 convertase
Biochem. J.
189
173-181
1980
Homo sapiens
Vogt, W.; Schmidt, G.; v.Buttlar, B.; Dieminger, L.
A new function of the activated third component of complement: binding to C5, an essential step for C5 activation
Immunology
34
29-40
1978
Homo sapiens
Porter, R.R.; Reid, K.B.M.
The biochemistry of complement
Nature
275
699-704
1978
Homo sapiens
Nicholson-Weller, A.; Burge, J.; Austen, F.
Purification from guinea pig erythrocyte stroma of a decay-accelerating factor for the classical C3 convertase, C4b2a
J. Immunol.
127
2035-2039
1978
Homo sapiens
Emmerling, M.R.; Spiegel, K.; Watson, M.D.
Inhibiting the formation of classical C3-convertase on the Alzheimer s beta-amyloid peptide
Immunopharmacology
38
101-109
1997
Homo sapiens
Sahu, A.; Rawal, N.; Pangburn, M.K.
Inhibition of complement by covalent attachment of rosmarinic acid to activated C3b
Biochem. Pharmacol.
57
1439-1446
1999
Homo sapiens
Bloch, E.F.; Rahbar, M.; Wright, A.K.; Patterson, A.M.; Souza, R.F.; Hammer, C.H.; Gaither, T.A.; Joiner, K.A.
Potassium cyanide protects Escherichia coli from complement killing by the inhibition of C3 convertase activity
Immunol. Invest.
22(2)
127-149
1993
Homo sapiens
-
Kerr, M.A.
The second component of human complement
Methods Enzymol.
80
54-64
1981
Homo sapiens
-
Fodor, W.L.; Rollins, S.A.; Guilmette, E.R.; Settler, E.; Squinto, S.P.
A novel bifunctional chimeric complement inhibitor that regulates C3 convertase and formation of the membrane attack complex
J. Immunol.
155
4135-4138
1995
Homo sapiens
Pangburn, M.K.; Rawal, N.
Structure and function of complement C5 convertase enzymes
Biochem. Soc. Trans.
30
1006-1010
2002
Homo sapiens
Rawal, N.; Pangburn, M.K.
Formation of high affinity C5 convertase of the classical pathway of complement
J. Biol. Chem.
278
38476-38483
2003
Homo sapiens
Kuttner-Kondo, L.A.; Dybvig, M.P.; Mitchell, L.M.; Muqim, N.; Atkinson, J.P.; Medof, M.E.; Hourcade, D.E.
A corresponding tyrosine residue in the C2/factor B type A domain is a hot spot in the decay acceleration of the complement C3 convertases
J. Biol. Chem.
278
52386-52391
2003
Homo sapiens
Blom, A.M.; Zadura, A.F.; Villoutreix, B.O.; Dahlback, B.
Positively charged amino acids at the interface between alpha-chain CCP1 and CCP2 of C4BP are required for regulation of the classical C3-convertase
Mol. Immunol.
37
445-453
2000
Homo sapiens
Krych-Goldberg, M.; Hauhart, R.E.; Porzukowiak, T.; Atkinson, J.P.
Synergy between two active sites of human complement receptor type 1 (CD35) in complement regulation: implications for the structure of the classical pathway C3 convertase and generation of more potent inhibitors
J. Immunol.
175
4528-4535
2005
Homo sapiens
Moller-Kristensen, M.; Thiel, S.; Sjoeholm, A.; Matsushita, M.; Jensenius, J.C.
Cooperation between MASP-1 and MASP-2 in the generation of C3 convertase through the MBL pathway
Int. Immunol.
19
141-149
2007
Homo sapiens
Mark, L.; Proctor, D.G.; Blackbourn, D.J.; Blom, A.M.; Spiller, O.B.
Separation of decay-accelerating and cofactor functional activities of Kaposis sarcoma-associated herpesvirus complement control protein using monoclonal antibodies
Immunology
123
228-238
2008
Homo sapiens
Kuttner-Kondo, L.; Hourcade, D.E.; Anderson, V.E.; Muqim, N.; Mitchell, L.; Soares, D.C.; Barlow, P.N.; Medof, M.E.
Structure-based mapping of DAF active site residues that accelerate the decay of C3 convertases
J. Biol. Chem.
282
18552-18562
2007
Homo sapiens
Jongerius, I.; Koehl, J.; Pandey, M.K.; Ruyken, M.; van Kessel, K.P.; van Strijp, J.A.; Rooijakkers, S.H.
Staphylococcal complement evasion by various convertase-blocking molecules
J. Exp. Med.
204
2461-2471
2007
Homo sapiens
Spitzer, D.; Mitchell, L.M.; Atkinson, J.P.; Hourcade, D.E.
Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly
J. Immunol.
179
2600-2608
2007
Homo sapiens
Krishnan, V.; Xu, Y.; Macon, K.; Volanakis, J.E.; Narayana, S.V.
The crystal structure of C2a, the catalytic fragment of classical pathway C3 and C5 convertase of human complement
J. Mol. Biol.
367
224-233
2007
Homo sapiens
Spiller, O.B.; Mark, L.; Blue, C.E.; Proctor, D.G.; Aitken, J.A.; Blom, A.M.; Blackbourn, D.J.
Dissecting the regions of virion-associated Kaposis sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding
J. Virol.
80
4068-4078
2006
Homo sapiens
Milder, F.J.; Raaijmakers, H.C.; Vandeputte, M.D.; Schouten, A.; Huizinga, E.G.; Romijn, R.A.; Hemrika, W.; Roos, A.; Daha, M.R.; Gros, P.
Structure of complement component C2A: implications for convertase formation and substrate binding
Structure
14
1587-1597
2006
Homo sapiens
Krishnan, V.; Xu, Y.; Macon, K.; Volanakis, J.E.; Narayana, S.V.
The structure of C2b, a fragment of complement component C2 produced during C3 convertase formation
Acta Crystallogr. Sect. D
65
266-274
2009
Homo sapiens
Rawal, N.; Rajagopalan, R.; Salvi, V.P.
Activation of complement component C5: comparison of C5 convertases of the lectin pathway and the classical pathway of complement
J. Biol. Chem.
283
7853-7863
2008
Homo sapiens
Katschke, K.J.; Stawicki, S.; Yin, J.; Steffek, M.; Xi, H.; Sturgeon, L.; Hass, P.E.; Loyet, K.M.; Deforge, L.; Wu, Y.; van Lookeren Campagne, M.; Wiesmann, C.
Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement
J. Biol. Chem.
284
10473-10479
2009
Homo sapiens
Laursen, N.S.; Gordon, N.; Hermans, S.; Lorenz, N.; Jackson, N.; Wines, B.; Spillner, E.; Christensen, J.B.; Jensen, M.; Fredslund, F.; Bjerre, M.; Sottrup-Jensen, L.; Fraser, J.D.; Andersen, G.R.
Structural basis for inhibition of complement C5 by the SSL7 protein from Staphylococcus aureus
Proc. Natl. Acad. Sci. USA
107
3681-3686
2010
Homo sapiens
Laursen, N.; Andersen, K.; Braren, I.; Spillner, E.; Sottrup-Jensen, L.; Andersen, G.
Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex
EMBO J.
30
606-616
2011
Homo sapiens (P01031)
Luo, S.; Hartmann, A.; Dahse, H.; Skerka, C.; Zipfel, P.
Secreted pH-regulated antigen 1 of Candida albicans blocks activation and conversion of complement C3
J. Immunol.
185
2164-2173
2010
Homo sapiens
Braunschweig, A.; Jozsi, M.
Human pentraxin 3 binds to the complement regulator c4b-binding protein
PLoS ONE
6
e23991
2011
Homo sapiens
Lee, M.; Guo, J.P.; McGeer, E.G.; McGeer, P.L.
Aurin tricarboxylic acid self-protects by inhibiting aberrant complement activation at the C3 convertase and C9 binding stages
Neurobiol. Aging
34
1451-1461
2013
Homo sapiens
Okroj, M.; Holmquist, E.; King, B.C.; Blom, A.M.
Functional analyses of complement convertases using C3 and C5-depleted sera
PLoS ONE
7
e47245
2012
Homo sapiens
Kim, H.; Meyer, K.; Di Bisceglie, A.M.; Ray, R.
Inhibition of C3 convertase activity by hepatitis C virus as an additional lesion in the regulation of complement components
PLoS ONE
9
e101422
2014
Homo sapiens
Zwarthoff, S.A.; Berends, E.T.M.; Mol, S.; Ruyken, M.; Aerts, P.C.; Jozsi, M.; de Haas, C.J.C.; Rooijakkers, S.H.M.; Gorham, R.D.
Functional characterization of alternative and classical pathway C3/C5 convertase activity and inhibition using purified models
Front. Immunol.
9
1691
2018
Homo sapiens
Fridkis-Hareli, M.; Storek, M.; Or, E.; Altman, R.; Katti, S.; Sun, F.; Peng, T.; Hunter, J.; Johnson, K.; Wang, Y.; Lundberg, A.S.; Mehta, G.; Banda, N.K.; Michael Holers, V.
The human complement receptor type 2 (CR2)/CR1 fusion protein TT32, a novel targeted inhibitor of the classical and alternative pathway C3 convertases, prevents arthritis in active immunization and passive transfer mouse models
Mol. Immunol.
105
150-164
2019
Homo sapiens
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