C3-convertase

C3 convertase (C4bC2b, formerly C4bC2a) belongs to family of

serine proteases and is necessary in innate immunity as a part of the
Classical-complement-
complement system which eventuate in opsonisation of particles, pathway C3/C5 convertase
release of inflammatory peptides, C5 convertase formation and cell Identifiers
lysis. EC 3.4.21.43 (https://www.q
C3 convertase can be used to refer to the form produced in the number mul.ac.uk/sbcs/iubmb/en
alternative pathway (C3bBb) or the classical and lectin pathways zyme/EC3/4/21/43.html)
(C4bC2b, formerly C4b2a). Once formed, both C3 convertases will CAS 56626-15-4 (http://www.c
catalyze the proteolytic cleavage of C3 into C3a and C3b (hence the number ommonchemistry.org/Ch
name "C3-convertase"). emicalDetail.aspx?ref=56
626-15-4&title=)
The smaller fragment called C3a serves to increase vascular
permeability and promote extravasation of phagocytes, while the Alt. C42 , C4bC2b (formerly
larger C3b fragment can be used as an opsonin or bind to either type names C4bC2a), C3bBb,
of C3 convertase to form the trimolecular C5 convertase to activate complement
C5 for the membrane attack complex. C.hivin.4.hivin2,
complement C3
convertase
Contents Databases

Formation IntEnz IntEnz view (https://www.

Alternative pathway ebi.ac.uk/intenz/query?c
Classical and lectin pathways md=SearchEC&ec=3.4.2
1.43)
Regulation
BRENDA BRENDA entry (http://ww
Location on chromosome
w.brenda-enzymes.org/e
References nzyme.php?ecno=3.4.2
External links 1.43)
ExPASy NiceZyme view (http://w
ww.expasy.org/enzyme/
Formation 3.4.21.43)

C3 convertase formation can occur in three different pathways: the KEGG KEGG entry (https://ww
classical, lectin, and alternative pathways. w.genome.jp/dbget-bin/w
ww_bget?enzyme+3.4.2
1.43)
Alternative pathway
MetaCyc metabolic pathway (http
Cleavage of complement C3 by a free floating convertase, s://biocyc.org/META/subs
thrombin, plasmin or even a bacterial enzyme leads to formation of tring-search?type=NIL&o
C3a and C3b fragments. C3b, the larger fragment, becomes bject=3.4.21.43)
covalently attached to the microbial surface or to the antibody PRIAM profile (http://priam.prabi.
molecules through the thioester domain at the site of complement fr/cgi-bin/PRIAM_profiles
activation. After cleavage and binding to cell surface, the C3b
fragment is ready to bind a plasma protein called Factor B. The
Factor B (a zymogen) is cleaved by a plasma serine protease Factor _CurrentRelease.pl?EC=
D releasing a small fragment called Ba and generating a larger 3.4.21.43)
fragment called Bb that remains attached to C3b. Also Mg2+ ions
PDB RCSB PDB (http://www.rc
are necessary for forming a functional C3 convertase. Thus, the
structures sb.org/pdb/search/smart
alternative C3 convertase (C3bBb) is formed and is able to cleave
C3 via its dimeric Bb subunit.[1][2] Subquery.do?smartSear
chSubtype=EnzymeClas
Since C3 convertases cleave C3 to produce C3b which can then sificationQuery&Enzyme
form an additional C3 convertase through the alternative pathway, _Classification=3.4.21.4
this is a potential mechanism of signal amplification in the 3) PDBe (https://www.eb
complement cascade resulting in the deposition of large numbers of i.ac.uk/pdbe/entry/searc
C3b molecules on the surface of activating particles, enabling
h/index?ec_number:3.4.
opsonisation and acute local inflammation.[3]
21.43) PDBsum (https://
www.ebi.ac.uk/thornton-s
Classical and lectin pathways rv/databases/cgi-bin/enz
ymes/GetPage.pl?ec_nu
The C3 convertase formed in the classical or lectin pathways is mber=3.4.21.43)
formed of C4b and C2b instead (NB: C2b, the larger fragment of
Search
C2 cleavage, was formerly known as C2a). The cleavage of C4 and
C2 is mediated by serine proteases. In the classical pathway, this is PMC articles (https://www.ncbi.nlm.ni
by sequential proteolytic activation of proteins within the C1 h.gov/entrez/query.fcgi?db=pub
complex (C1q, C1r, C1s) in response to binding to CRP or med&term=3.4.21.43%5BEC/R
N%20Number%5D%20AND%
immunoglobulin, and in the lectin pathway it is driven by mannose
20pubmed%20pmc%20local%
binding lectin and its associated serine proteases (MASPs,
5Bsb%5D)
particularly MASP2 but also MASP1).
PubMed articles (https://www.ncbi.nlm.ni
C4 is homologous to C3 in that it contains an internal thioester bond h.gov/entrez/query.fcgi?db=pub
that ends up on C4b. Thus it can form covalent amide or ester med&term=3.4.21.43%5BEC/R
linkages with the plasma membrane of the pathogen and any N%20Number%5D)
associated antibodies, where it then behaves as an opsonin. The NCBI proteins (https://www.ncbi.nlm.n
larger C2b produced by C2 hydrolysis attaches to the C4b to form ih.gov/protein?term=3.4.21.4
the classical C3 convertase, C4b2b (formerly called C4b2a).[4] 3%5BEC/RN%20Number%5D)

The smaller fragments of proteolysis, C4a and C2a are released. C4a is an anaphylatoxin.[1]

Regulation
C3 convertases are unstable (half-life 10 – 20 min) – respectively they are deactivated upon
spontaneous dissociation or by facilitated dissociation mediated by the regulators of
complement activation proteins decay accelerating factor (DAF), complement receptor 1 (CR1),
C4b-binding protein and Factor H. Convertase assembly is suppressed by the proteolytic
cleavage of C3b (and C4b) as mediated by Factor I in the presence of membrane cofactor
protein (MCP, CD46), C4b-binding protein, CR1, or a plasma-glycoprotein Factor H. These
negative control processes are essential for the protection of self-tissue.[5]
Properdin (Factor P) is the only known positive regulator of complement activation that
stabilizes the alternative C3 convertase (C3bBb). Properdin deficient individuals are sensitive
to pyogenic infections. Properdin also promotes association of C3b with Factor B and thus it
inhibits the Factor H mediated cleavage of C3b by Factor I.[6]
Nevertheless, this positive feedback mechanism can be
regulated by binding of the control protein, nonproteolytic
glycoprotein β1H (factor H), to C3b, which prevents
association of factor B, and facilitates the decay-dissociation
of Bb in the C3bBb complex, in addition to enhancing
proteolytic inactivation of C3b by C3b inactivator (C3bINA –
endopeptidase).

Membrane-associated sialic acid promotes high-affinity

binding of β1H to C3b without influencing the affinity of B
for C3b.

Decay-accelerating factor (DAF) is another negative

regulator of C3 convertase. It is a membrane protein and
regulates also C5 convertase of the classical and alternative
pathway. DAF protects host cells from damage by autologous
complement. DAF acts on C2b and Bb and dissociates them
rapidly from C4b and C3b – thereby preventing the assembly
of the C3 convertase.[7] The classical and alternative complement
pathways.
C4 binding protein (C4BP) interferes with the assembly of
the membrane-bound C3 convertase of the classical pathway.
C4BP is a cofactor for the enzyme C3bINA. C4b-binding
protein inhibits the haemolytic function of cell-bound C4b.
C4b-binding protein and C3b inactivator control the C3
convertase of the classical pathway in a similar way to that
described for β1H and C3b inactivator in the alternative
pathway.[8]

C3b has different binding site for C3bINA, β1H, factor B and
properdin. Binding β1H to C3b increases C3bINA binding,
while factor B binding prevents C3bINA binding and is
competitive with β1H binding.[9]

Regulation of the amplification phase of the alternative

pathway is exerted by multiple mechanisms:

Intrinsic decay of C3 convertase

Stabilization of C3 convertase by properdin
Disassembly of this enzyme by serum glycoprotein
β1H
Inactivation of C3b
Protection of C3 convertase from the activation of Complement-pathways.
these control proteins afforded by the surface
properties of certain cells and other activators of the
alternative pathway.

Location on chromosome
The genes encoding C2, C4 and factor B are located on chromosome 6 between the B locus of class I
products and the D locus of class II products in the MHC.
References
1. Abbas AK, Lichtman AH, Pillai S (2010). Cellular and Molecular Immunology (https://archive.or
g/details/cellularmolecula00abba_1) (6th ed.). Elsevier. ISBN 978-1-4160-3123-9.
2. Smith C, Vogel C-W, Müller-Eberhard H (1984). "MHC Class III Products: An Electron
Microscopic Study of the C3 Convertases of Human Complement" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC2187187). J Exp Med. 159 (1): R324–329. doi:10.1084/jem.159.1.324 (http
s://doi.org/10.1084%2Fjem.159.1.324). PMC 2187187 (https://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC2187187). PMID 6559206 (https://pubmed.ncbi.nlm.nih.gov/6559206).
3. Pangburn, M K; Schreiber, R D; Müller-Eberhard, H J (1 October 1983). "C3b deposition during
activation of the alternative complement pathway and the effect of deposition on the activating
surface". The Journal of Immunology. 131 (4): 1930–1935. PMID 6225800 (https://pubmed.ncb
i.nlm.nih.gov/6225800).
4. Kozlov, L. V; Shibanova, E. D; Zinchenko, A. A (1987). "Formation of classical C3 convertase
during the alternative pathway of human complement activation". Biokhimiia (Moscow, Russia).
52 (4): 660–6. PMID 3647798 (https://pubmed.ncbi.nlm.nih.gov/3647798).
5. Hourcade D, Holers VM, Atkinson JP (1989). "The regulators of complement activation (RCA)
gene cluster". Adv Immunol. Advances in Immunology. 45: R381–416. doi:10.1016/s0065-
2776(08)60697-5 (https://doi.org/10.1016%2Fs0065-2776%2808%2960697-5).
ISBN 9780120224456.
6. Hourcade D (2006). "The Role of Properdin in the Assembly of the Alternative Pathway C3
Convertases of Complement" (https://doi.org/10.1074/jbc.m508928200). J Biol Chem. 281 (4):
R2128–2132. doi:10.1074/jbc.m508928200 (https://doi.org/10.1074%2Fjbc.m508928200).
PMID 16301317 (https://pubmed.ncbi.nlm.nih.gov/16301317).
7. Fujita T; et al. (1987). "The Mechanism of Action of Decay-Accelerating Factor (DAF)" (https://w
ww.ncbi.nlm.nih.gov/pmc/articles/PMC2189641). J Exp Med. 166 (5): R1221–1228.
doi:10.1084/jem.166.5.1221 (https://doi.org/10.1084%2Fjem.166.5.1221). PMC 2189641 (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC2189641). PMID 2445886 (https://pubmed.ncbi.nlm.
nih.gov/2445886).
8. Gigli I, Fujita T, Nussenzweig V (1979). "Modulation of the Classical Pathway C3 Convertase
by Plasma Proteins C4 Binding Protein and C3b Inactivator" (https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC411913). Proc Natl Acad Sci USA. 76 (12): R6596–6600.
doi:10.1073/pnas.76.12.6596 (https://doi.org/10.1073%2Fpnas.76.12.6596). PMC 411913 (http
s://www.ncbi.nlm.nih.gov/pmc/articles/PMC411913). PMID 293746 (https://pubmed.ncbi.nlm.ni
h.gov/293746).
9. Pangburn M, Müller-Eberhard H (1978). "Complement C3 Convertase: Cell surface restriction
of β1H control and generation of restriction on neuroaminidase-treated cells" (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC392564). Proc Natl Acad Sci USA. 75 (5): R2416–2420.
doi:10.1073/pnas.75.5.2416 (https://doi.org/10.1073%2Fpnas.75.5.2416). PMC 392564 (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC392564). PMID 276881 (https://pubmed.ncbi.nlm.nih.g
ov/276881).

External links
C3+convertase (https://meshb.nlm.nih.gov/record/ui?name=C3%20convertase) at the US
National Library of Medicine Medical Subject Headings (MeSH)

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