Classical complement pathway
Complement system is a major effector of the humoral branch of the immune system,
acting to protect the host from microorganisms such as bacteria.
Complement components are designated by numerals
(C1-C9), by letter symbols
(e.g., Complement factor I (Factor I)), or by trivial names.
Peptide fragments formed by activation of a component are denoted by small letters , .
In most cases, the smaller fragment resulting from cleavage of a Complement component
is designated 'a' and the larger fragment designated 'b' (e.g.,
C3a, C3b; note that Complement
component C2 is an exception:
C2a is the larger cleavage fragment) .
Larger fragments bind to targets near activation sites, while smaller fragments,
called anaphylatoxins, diffuse from the site and may initiate localized inflammatory
responses by binding to specific receptors, such as Complement component 3a receptor 1
Complement component 5a receptor 1 (CR5aR)
, , . Complement fragments named
opsonins, i.e., C1q, C3b,
C3dg, and iC3b, interact with
the cell surface receptors, such as CD93 molecule
(C1qRp), Complement component
receptor 1 (CR1), Complement
component receptor 2 (CD21), Integrins
alpha-M/beta-2 integrin and alpha-X/beta-2
integrin, to promote phagocytosis , .
Complement fragments interact with each another to form functional complexes.
Complement activation by the classical pathway commonly begins with the formation of
soluble antigen-antibody complexes (immune complexes) or with the binding of antibody
(Immunoglobulins such as IgG1 and
IgM) to antigen on a suitable target, such as a bacterial
Initial stage of activation involves Complement components
C1, C2, C3 and
C4, which are present in plasma in functionally inactive
Formation of an antigen-antibody complex induces conformational changes in the Fc part
of the IgM molecule that expose a binding site for the
Complement component C1. C1 in
serum is represented by a macromolecular complex (also called C1qr2s2). It consists of
three protein subunits Complement component 1 q subcomponent
(C1q), Complement component 1 r subcomponent
(C1r) and Complement component 1 s subcomponent
(C1s). Components of complex are stabilized by Ca(2+) ions
Serpin peptidase inhibitor clade G member 1 (C1
inhibitor) inhibits activated C1r and
C1s and thus regulates complement activation .
C1r cleaves and activates
C1s, which translates the activation of the Complement
component C1 complex into complement activation via cleavage
of C4 and C2 to form a
C3 convertase (C2aC4b). C3 convertase
(C2aC4b) cleaves C3.
C5 convertase (C2aC4bC3b) involved in classical pathway
is assembled of two proteins, C4b and
C2a, and additional
C3b molecules. CD55 molecule decay accelerating factor for
complement (DAF) inhibits the assembly of the complement
system C3/C5 convertases by complex formation with C4b and
C3b , .
Factor I is a major regulator of complement. As a
protease it has very restricted specificity, cleaving only C3b
or C4b in the presence of a cofactor such as
Complement factor H (Factor H).
Cleavage of C3b by Factor I
yields iC3b, a major opsonin . CD46
molecule, complement regulatory protein (MCP) is a cofactor
for the Factor I -mediated degradation of C3b and
C4b deposited on host cells .
Smaller fragments resulting from complement cleavage, C3a
and C5a, called anaphylatoxins, bind to their
cognate receptors (CR3aR and
CR5aR) on the surface of mast cells and blood basophils and induce
degranulation, upon release of histamine and other biologically active mediators .
The terminal sequence of complement activation involves Complement
components C5b, C6,
C7, C8, and
C9, which interact sequentially to form a macromolecular
structure called Membrane attack complex. This complex
creates pores in the cell membrane and induces cell lysis.
C5b initiates assembly of Membrane attack
complex by binding of C6 and
C7 resulting in C5b/C6/C7 hydrophobic complex. It inserts
into the lipid bilayer of cell membranes, where it becomes a high-affinity receptor for
C8 molecules (C8alpha, C8beta,
C8gamma). C5b/C6/C7/C8 complex has a limited ability to lyse
cells. The formation of fully active Membrane attack complex
is accomplished by binding of C9 to C5b/C6/C7/C8 complex.
This fully active Membrane attack complex forms a large
channel through the membrane of the target cell, enabling ions and small molecules to
diffuse freely across the membrane .
The latest step of complement activation is also controlled by the membrane-associated
complement regulatory protein CD59 that prevents the
formation of the Membrane attack complex at the terminal
step of complement activation cascade , . Plasma
complement regulatory protein Clusterin can also interfere
with formation of the Membrane attack complex pore 
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