Nomenclature and general principles of activation
Activation of complement system factors occurs via their cleavage. This results in the formation of two types of fragments, which are designated by lowercase letters added to the name of the original component:
- Large fragment («b»): possesses enzymatic (protease or esterase) activity. It is firmly fixed on the target cell membrane, embeds into active complexes, and directly continues the cascade (e.g., C3b, C4b, C5b).
- Small fragment («a»): lacks enzymatic activity and does not participate in the further cleavage of components. Instead, these peptides act as potent inflammatory mediators—possessing chemotactic and vasodilating (kinin) activity as they diffuse into surrounding tissues (e.g., C3a, C4a).
Exception: the a/b rule in its standard form does not apply only to the C4 component.
Central C3 molecule and the thioester bond
The C3 molecule is a crucial component of the cascade, chemically classified as an $\alpha$-globulin. Like C4 and C5 proteins, it belongs to the C3/$\alpha_2$-macroglobulin family.
The primary structural feature of proteins in this family is the presence of a thioester bond between glutamic acid and cysteine amino acid residues (this bond was lost in the C5 molecule during phylogeny).
Mechanism of the thioester bond:
- In the native (intact) C3 molecule, this bond is reliably shielded and inaccessible to surrounding water molecules.
- When an enzyme (C3 convertase) cleaves off the small C3a fragment, the conformation of the remaining large C3b fragment changes, and the thioester bond is unmasked.
- The released carboxyl group ($COOH$) instantly forms a strong covalent bond with $NH_2$ groups of proteins on the pathogen membrane.
- If no membrane is nearby, the bond is irreversibly hydrolyzed by water, and the molecule loses its ability to bind.
Structure of initiating molecules: «bouquet of tulips»
The classical and lectin activation pathways are triggered by large macromolecular complexes that are structurally very similar, although they share low homology. The recognition molecules C1q (classical pathway) and MBL (lectin pathway) belong to the collectin family.
Their spatial configuration resembles a «bouquet of tulips»:
- The «stem» of the bouquet is formed by helically intertwined N-terminal collagen-like domains.
- The branches and buds are formed by globular C-terminal parts of the chains diverging outward. These are precisely what mediate ligand binding.
For C1q, such a ligand is represented by the constant domains of immunoglobulins (antibodies) within immune complexes. For MBL, they are carbohydrate patterns (lectins, mannose) on the microbial surface. Upon target recognition, associated serine proteases (C1r/C1s or MASP-1/MASP-2) are activated, initiating the subsequent proteolytic cascade.
Alternative pathway: «self-nonself» recognition
The alternative pathway is phylogenetically the most ancient and operates within innate immunity without the participation of antibodies. It is triggered by the spontaneous hydrolysis of the C3 molecule in blood serum. With the participation of factors B and D, an enzyme is formed — the alternative pathway C3 convertase (C3bBb complex).
Since this process occurs continuously, the body requires strict control to prevent the convertase from destroying its own cells. The defense mechanism is based on the presence of specific carbohydrates on cell membranes:
- Host cells contain sialic acid residues. These allow the regulatory factor H to bind to the surface and displace the active Bb fragment from the complex, after which factor I finally cleaves C3b.
- Microorganisms lack sialic acids. The C3bBb complex remains stable on their surface. This is additionally facilitated by properdin (factor P), which binds to the bacterial membrane, protects the convertase from factor H, and greatly increases its half-life, leading to potent opsonization of the bacterium.
Briefly: answers to topical questions
Which proteins comprise the membrane attack complex (MAC)?
The membrane attack complex (MAC) comprises components of the terminal phase of the complement cascade from C5b to C9.
- C5b — fixes to the cell membrane and serves as the assembly initiator.
- C6 — binds to the C5b fragment.
- C7 — binds to the complex following C6.
- C8 — joins the C5b-C7 complex, forming an anchor for polymerization.
- C9 — multiple molecules polymerize on the C5b-C8 complex, forming a transmembrane pore.
Which components form the classical pathway C3 convertase?
The classical pathway C3 convertase is formed by fragments of complement components C4 and C2:
- C4b — a C4 fragment that binds to the target cell surface.
- C2a — a C2 fragment that associates with C4b.
Complex formula: C4b2a.
Which complement fragments are anaphylatoxins?
Anaphylatoxins include fragments of complement system components C3a, C4a, and C5a.
- C3a — a small fragment cleaved from the α-chain of C3.
- C4a — a fragment formed during the cleavage of C4 by the C1qrs complex.
- C5a — an anaphylatoxin formed during the cleavage of C5.
C3a and C5a induce vascular changes and attract leukocytes to the site of inflammation.
It is easy to get confused in fragment nomenclature. Remember the basic rule: b is the big [large] fragment (remains functioning on the target cell membrane), while a is the active mediator that enters the bloodstream to induce inflammation (with the exception of the C4 component).
Class and exam questions
Where are complement system proteins synthesized?
Hepatocytes are the primary source (up to 90% of all factors). Extrahepatic synthesis is characteristic of factor D (adipose tissue) and component C7 (neutrophils). During inflammation, their production is upregulated by cytokines.
What is the function of properdin (factor P)?
Properdin stabilizes the alternative pathway C3 convertase complex (C3bBb) on the bacterial surface. It attenuates spontaneous dissociation of the enzyme and prevents its degradation by factor H, enhancing complement fixation on the pathogen.
Which antibodies does the C1q component interact with?
To trigger the classical pathway, C1q must bind to the constant domains of immunoglobulins that underwent conformational change following antigen binding. This involves IgM molecules, as well as IgG1, IgG3, and, to a lesser extent, IgG2.
What domains are found in complement system proteins?
Domains of the C3/α2-macroglobulin family (with a thioester bond), complement control protein modules (CCP, characteristic of regulatory proteins), and serine protease modules (present in factors B, D, I, C2, and MASP proteins) are distinguished.
What else to study on this topic
- Stages of C3b inactivation: cleavage into C3dg, C3f, C3d, and soluble C3c fragments.
- Amplification phase of the alternative activation pathway and the role of magnesium ions.
- Lytic cascade proteins (C5–C9) and their structural similarity to perforin.
- Cross-talk of pathways: participation of classical pathway products in the alternative cascade.
- Characteristics of membrane complement regulators: DAF (CD55) and the CR1 receptor.
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