Key Complement System Proteins

Why This Matters

The complement system is one of the most elegant examples of a proteolytic cascade in immunology—a molecular domino effect where each activated protein triggers the next, amplifying the immune response exponentially. You're being tested on how this system bridges innate and adaptive immunity, generates inflammation, enables opsonization, and directly kills pathogens through membrane attack. Understanding complement means understanding how the body creates a coordinated, multi-pronged assault on invaders without waiting for T cells or B cells to respond.

Don't just memorize protein names and numbers. Know which pathway each protein belongs to, what enzymatic reaction it catalyzes or undergoes, and what effector function it contributes to. The exam loves asking you to trace a pathway from initiation to lysis, compare how different pathways converge, or explain what happens when specific components are deficient. Master the logic of the cascade, and the individual proteins will make sense.

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Pathway Initiators: Recognition Molecules

These proteins are the sentinels that detect "danger" and kick off complement activation. Each pathway uses a different recognition strategy—antibody binding, lectin-carbohydrate interactions, or spontaneous C3 hydrolysis—but all converge on the same downstream effectors.

C1 Complex (C1q, C1r, C1s)

• Initiates the classical pathway by binding to antibody-antigen complexes on pathogen surfaces—this is how adaptive immunity activates complement
• C1q is the recognition subunit that binds IgG or IgM; C1r and C1s are serine proteases that activate sequentially upon C1q binding
• Cleaves C4 and C2 to generate the classical pathway C3 convertase ($C4b2a$), launching the cascade

Mannose-Binding Lectin (MBL)

• Pattern recognition receptor that binds mannose and other carbohydrates commonly found on bacterial and fungal surfaces
• Activates the lectin pathway by associating with MBL-associated serine proteases (MASPs), which function analogously to C1r/C1s
• Bridges innate immunity and complement—no antibodies required, making it critical for early defense before adaptive responses develop

Ficolins

• Recognize acetylated carbohydrates (like $N$-acetylglucosamine) on pathogen surfaces—a different carbohydrate pattern than MBL targets
• Activate the lectin pathway through the same MASP-dependent mechanism as MBL
• Provide redundancy in innate recognition—multiple lectins ensure pathogens can't easily evade complement activation

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Alternative Pathway Amplifiers

The alternative pathway doesn't wait for recognition—it's always "ticking" at low levels through spontaneous C3 hydrolysis. These proteins amplify that baseline activity specifically on pathogen surfaces, creating a powerful feedback loop.

Factor B

• Binds to surface-bound C3b to form the proenzyme complex $C3bB$, which is then cleaved by Factor D
• Bb fragment remains attached to C3b, forming the alternative pathway C3 convertase ($C3bBb$)
• Drives the amplification loop—each C3bBb generates more C3b, which recruits more Factor B, exponentially increasing opsonization

Factor D

• Serine protease that cleaves Factor B only when B is bound to C3b—this specificity prevents uncontrolled activation in plasma
• Rate-limiting enzyme of the alternative pathway; present in plasma at low concentrations
• Essential for amplification—without Factor D, the alternative pathway cannot generate C3 convertase

Properdin (Factor P)

• Stabilizes the C3bBb convertase by binding to it and extending its half-life on pathogen surfaces
• Only positive regulator of complement—most regulatory proteins inhibit the cascade, but properdin enhances it
• Targets the amplification loop to pathogens—properdin binds preferentially to microbial surfaces, ensuring amplification happens where it's needed

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The Central Hub: C3 and Its Convertases

C3 is where all three pathways converge. Its cleavage into C3a and C3b is the most important single event in complement activation—it generates opsonins, anaphylatoxins, and the platform for MAC assembly.

C3

• Central component of all three pathways—classical, lectin, and alternative pathways all generate C3 convertases that cleave C3
• C3b is the major opsonin that covalently attaches to pathogen surfaces, marking them for phagocytosis via complement receptors
• C3b also forms C5 convertase by joining existing C3 convertases ($C4b2a3b$ or $C3bBb3b$), advancing the cascade toward lysis

C4

• Cleaved by C1s or MASPs into C4a (anaphylatoxin) and C4b (opsonin that binds covalently to surfaces)
• C4b combines with C2a to form the classical/lectin pathway C3 convertase ($C4b2a$)
• Deficiency linked to autoimmunity—without C4, immune complexes aren't cleared properly, increasing risk of lupus-like disease

C2

• Cleaved by C1s or MASPs into C2a and C2b; C2a is the enzymatic subunit that cleaves C3
• Forms the C3 convertase $C4b2a$ with C4b—this complex is essential for classical and lectin pathway progression
• Amplification checkpoint—the amount of C3 convertase generated determines how much C3b is deposited

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Terminal Pathway: The Membrane Attack Complex

Once C5 is cleaved, the cascade shifts from enzymatic cleavage to protein assembly. C5b through C9 form a physical pore in the target membrane—no enzymes required, just sequential protein recruitment and insertion.

C5

• Cleaved by C5 convertase into C5a (potent anaphylatoxin) and C5b (initiates MAC assembly)
• C5a is the strongest chemotactic factor in the complement system, recruiting neutrophils and macrophages to infection sites
• C5b is unstable and must quickly bind C6 or it loses activity—this prevents MAC formation away from target surfaces

C6

• Binds to C5b immediately after cleavage, forming the stable $C5b6$ complex
• Keeps C5b active and creates a platform for C7 recruitment
• No enzymatic activity—C6 is purely structural, stabilizing the growing MAC complex

C7

• Binds to C5b6 and undergoes a conformational change that exposes a hydrophobic domain
• Inserts into the target membrane—this is the first component that actually penetrates the lipid bilayer
• Commits the MAC to a specific membrane—once C7 inserts, the complex is anchored and cannot dissociate

C8

• Binds to membrane-inserted C5b67 and penetrates deeper into the bilayer
• Initiates pore formation by creating a small channel that begins to disrupt membrane integrity
• Recruits and catalyzes C9 polymerization—C8 is essential for the final lytic step

C9

• Polymerizes to form the complete MAC pore—up to 18 C9 molecules can assemble into a ring structure
• Creates a large transmembrane channel (approximately 10 nm diameter) that allows ions and water to flow freely
• Causes osmotic lysis—the target cell cannot maintain ion gradients and swells until it bursts

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Inflammatory Mediators: Anaphylatoxins

These small cleavage fragments don't participate in opsonization or lysis—instead, they diffuse away from the activation site and orchestrate the inflammatory response by signaling to immune cells and blood vessels.

C3a and C5a (Anaphylatoxins)

• Released during C3 and C5 cleavage—their production indicates active complement activation at an infection site
• C3a increases vascular permeability and causes smooth muscle contraction; C5a does this plus powerful chemotaxis
• Bind to G protein-coupled receptors (C3aR and C5aR) on mast cells, neutrophils, and macrophages, triggering degranulation and migration

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Quick Reference Table

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Self-Check Questions

1. Which two proteins serve analogous recognition functions in different pathways, and what distinguishes the molecules they recognize?

2. Trace the alternative pathway amplification loop: starting with spontaneous C3 hydrolysis, which proteins are required to generate more C3b, and what stabilizes the convertase?

3. Compare and contrast C3a and C5a—what inflammatory functions do they share, and what makes C5a the more potent mediator?

4. A patient has a genetic deficiency in C3. Explain why this affects all three complement pathways and which effector functions would be lost.

5. If an FRQ asks you to explain how complement directly kills gram-negative bacteria, which proteins would you discuss and in what order are they recruited to the target membrane?