Lecture 4: Complement Flashcards
Mention the components of the complement pathway.
“a” symbolizes the __________ fragment, while “b” symbolizes the ____________ fragment.
smaller, larger
Activation of the complement system typically occurs on ____________.
the surface of pathogen (usually not in healthy cells)
Host cell surface proteins regulate _____________.
complement activation (minimize host damage)
Soluble complement components are often ___________.
inactive or transiently active
Recall the overview of the complement activation
Recall the C3 and C5 convertases in the complement pathways.
Describe the alternative pathway complement activation.
C3 undergoes spontaneous hydrolysis to C3(H20), which then binds to factor B, allowing it to be cleaved by factor D into Ba and Bb. The C3(H20) complex is a C3 convertase, cleaving C3 into C3a and C3b. Factor B then binds noncovalently to C3b on a cell’s surface and is cleaved to Bb by factor D.
Pathogen lack complement-regulatory proteins. The binding of properdin (factor P) stabilizes the C3bBb complex, which is a C3 convertase and deposits many molecules of C3b on the pathogen surface, leading to opsonization and activation of terminal complement compounds.
Recall the protein of the alternative pathway of complement activation
Describe the initiation of the lectin pathway complement activation.
MBL monomers form a trimeric cluster of carbohydrate-recognition domains. This binds with high avidity to mannose and glucose residues. (Note that ficolins also exist but binds with oligosaccharides containing acetylated sugars)
Describe the formation of the C3 convertase in lectin pathway.
Activated MASP-2 associated with MBL or ficolin cleaves C4 to C4a and C4b, which binds to the microbial surface. C4b then binds C2, which can be cleaved by the MASP-2 to C2a, forming the C4b2a complex. This complex is an active C3 convertase, cleaving C3 to C3a and C3b, which binds to the microbial surface or to the convertase itself.
Describe the initiation of the classical pathway of complement activation.
It involves the “pathogen sensing complex”, C1. By binding to either antibodies (IgM, IgG) that have bound pathogens or C reactive protein (bind phosphocholine residues on bacterial surface), the C1q can be activated. This then induces C1r to cleave C1s to create an active serine protease.
Note that C1q can’t bind to soluble IgM or IgG. It requires an antigen-bound IgM or 2 or more antigen-bound IgG to activate C1.
Describe the formation of the C3 convertase in the classical pathway.
After the initiation, C4 binds to the Ig-bound C1q, where the activated C1s (serine protease) cleaves the C4 into C4a and C4b. C4b binds covalently to the surface and binds with C2. C1s then cleaves C2, forming the C4b2a complex (C3 convertase).
Describe how the classical and lectin pathway could lead to the amplification loop of the alternative pathway.
Recall the proteins of the classical and lectin pathway.
Describe the formation of the C5 convertase in the alternative pathway.
3b generated by the C3 convertase binds to itself to form the C5 convertase (C3bBbC3b), which cleaves C5 into C5a and C5b.
Describe the mechanism of the MAC formation.
Cleaved C5b is cell-bound and binds to C6 and C7 (hydrophobic). The C5bC6C7 complex inserts into the cell membrane and binds with C8. Note that C8 is a trimer, of which 1 unit inserts into the membrane. The C5bC6C7C8 complex cause the polymerisation of C9, forming the membrane attack complex (MAC). It consists of a 100 A pore and promotes cell death by osmotic rupture and apoptosis.
Describe the spontaneous tick over of C3.
The alternative pathway is capable of autoactivation because of a process termed “tickover” of C3. Tickover occurs spontaneously,, generating a conformationally altered C3, designated C3(H2O), that is capable of binding factor B. Once factor B associates with C3(H2O), factor B itself changes conformation and can then be cleaved by the constitutively active serum protease factor D, generating Ba and Bb. The Bb fragment remains associated with the complex and is itself a C3 convertase.
