| Themes > Science > Life Sciences > General Biology > Immunology > The Complement System > C3 is THE key component of Complement |
The central component of the complement system is C3. C3 is an abundant serum protein (1.2mg/ml) which contains an unusual internal thiolester bond. In native C3 this bond is stable but this thiolester bond can become highly reactive as a result of conformational changes in the C3 protein structure. Generally the activation of C3 comes about as a result of proteolytic cleavage of the C3 molecule into 2 biologically active fragments. |
| The Alternative Pathway The alternative pathway(AP) is an innate immune mechanism which exploits the properties of C3.  Initiation of the AP relies on the generation of an activated C3 molecule. There are various ways in this initiating activated C3 can be generated. These include proteolysis by enzymes derived from bacteria themselves and, via blood clotting enzymes, injury. However activation of C3 can occur spontaneously. This process proceeds constitutively at a slow rate. The activated thiolester will normally be rapidly hydrolysed in solution. Click here to see an animated GIF showing these reactions But if C3 binds via its ester bond to a cell surface or protein complex, it can recruit the AP serum protein factor B. Factor B, once bound to activated C3, is cleaved by another serum protein, factor D, and the resulting complex forms an enzyme which activates further C3 molecules by cleaving them to form the activated fragment C3b (plus C3a). Click here to see an animated version of this process At this point the Alternative Pathway becomes self-generating by a positive feedback loop, those activated C3b molecules which are not quenched by hydrolysis binding to nearby surfaces, recruiting factors B and D and generating the C3bBb complex which in turn cleaves more C3 etc. The complex C3bBb is known as the alternative C3 convertase. This complex is a short-lived one, but is stabilised on certain microbial surfaces by binding of the serum factor Properdin (P). |
| The Classical Pathway
The classical activation pathway is triggered when a molecule of C1 binds the an antibody-antigen complex. C1 is a complex of 1 C1q,2C1r and 2 C1s subunits; C1q has 6 binding sites for IgFc. The affinity of a single C1q binding site for 1 Fc is low so that at least 2 sites are required for stable binding of C1q and subsequent activation of C1r. This requires 2 juxtaposed IgGs or a distorted IgM, thus free IgG and IgM do not activate complement. Click here to see a cartoon of C1q binding to IgM and IgG complexes Activated C1r cleaves C1s to generate the
active C1s protease which in turn cleaves first C4 (to C4a +C4b) and,
after C2 has bound C4b, C2 to generate C4bC2a, the classical C3
convertase. C4b contains a highly reactive (i.e.
short-lived) thiol-ester bond which is capable of forming a
covalent attachment to nearby proteins and carbohydrates on immune
complexes, cell and bacterial surfaces. Convergence of the Classical and Alternative Pathways Click here to see a
summary of the complement cascade |
| The C3 convertases are powerful amplifiers of complement activation, up to 1000 C3 molecules are cleaved to C3b by each molecule of active C3 convertase. Each C3 convertase can be converted into a C5 convertase by the binding of a C3b molecule; this subsequently splits C5 into C5b and C5a. |
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