The Three Complement Pathways Converge at the Membrane Attack Complex

The terminal sequence of complement activation involves C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called the membrane-attack complex (MAC). This complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane.

The end result of activating the classical, alternative, or lectin pathways is production of an active C5 convertase. This enzyme cleaves C5, which contains two protein chains, a and p. After binding of C5 to the nonenzymatic C3b component of the convertase, the amino terminus of the a chain is cleaved. This generates the small C5a fragment, which diffuses away, and the large C5b fragment, which binds to the surface of the target cell and provides a binding site for the subsequent components of the membrane-attack complex (see Figure 13-5, step 5). The C5b component is extremely labile and becomes inactive within 2 minutes unless C6 binds to it and stabilizes its activity.

Up to this point, all the complement reactions take place on the hydrophilic surface of membranes or on immune complexes in the fluid phase. As C5b6 binds to C7, the resulting complex undergoes a hydrophilic-amphiphilic structural transition that exposes hydrophobic regions, which serve as binding sites for membrane phospholipids. If the reaction occurs on a target-cell membrane, the hydrophobic binding sites enable the C5b67 complex to insert into the phospho-lipid bilayer. If, however, the reaction occurs on an immune

VISUALIZING CONCEPTS

VISUALIZING CONCEPTS

C3 hydrolyzes spontaneously, C3b fragment attaches to foreign surface

Factor B binds C3a, exposes site acted on by Factor D. Cleavage generates C3bBb, which has C3 convertase activity

Binding of properdin stabilizes convertase

Convertase generates C3b; some binds to C3 convertase activating C5' convertase. C5b binds to antigenic surface

C3b C3a

Factor B

Factor D

C3bBb + Properdin C3 convertase o

C3bBb + Properdin C3 convertase

C3bBb3B C3 convertase

Membrane attack complex

FIGURE 13-7

Schematic diagram of intermediates in the formation of bound C5b by the alternative pathway of complement activation. The C3bBb complex is stabilized by binding of prop erdin. Conversion of bound C5b to the membrane-attack complex occurs by the same sequence of reactions as in the classical pathway (see Figure 13-5).

complex or other noncellular activating surface, then the hydrophobic binding sites cannot anchor the complex and it is released. Released C5b67 complexes can insert into the membrane of nearby cells and mediate "innocent-bystander" lysis. Regulator proteins normally prevent this from occurring, but in certain diseases cell and tissue damage may result from innocent-bystander lysis. A hemolytic disorder resulting from deficiency in a regulatory protein is explained in the Clinical Focus section and an autoimmune process in which immune complexes mediate tissue damage will be considered in Chapter 20.

Binding of C8 to membrane-bound C5b67 induces a conformational change in C8, so that it too undergoes a hy-drophilic-amphiphilic structural transition, exposing a hydrophobic region, which interacts with the plasma membrane. The C5b678 complex creates a small pore, 10 Â in diameter; formation of this pore can lead to lysis of red blood cells but not of nucleated cells. The final step in formation of the MAC is the binding and polymerization of C9, a per-forin-like molecule, to the C5b678 complex. As many as 10-17 molecules of C9 can be bound and polymerized by a single C5b678 complex. During polymerization, the C9 molecules undergo a hydrophilic-amphiphilic transition, so that they too can insert into the membrane. The completed MAC, which has a tubular form and functional pore size of 70-100 A, consists of a C5b678 complex surrounded by a poly-C9 complex (Figure 13-8). Since ions and small molecules can diffuse freely through the central channel of the MAC, the cell cannot maintain its osmotic stability and is killed by an influx of water and loss of electrolytes.

Complement Structure

FIGURE 13-8

(a) Photomicrograph of poly-C9 complex formed by in vitro polymerization of C9. (b) Photomicrograph of complement-induced lesions on the membrane of a red blood cell. These lesions result from formation of membrane-attack complexes. [Part (a) from E. R. Podack, 1986, in Immunobiology of the Complement System, Academic Press; part (b) from J. Humphrey and R. Dourmashkin, 1969, Adv. Immunol. 11:75.]

FIGURE 13-8

(a) Photomicrograph of poly-C9 complex formed by in vitro polymerization of C9. (b) Photomicrograph of complement-induced lesions on the membrane of a red blood cell. These lesions result from formation of membrane-attack complexes. [Part (a) from E. R. Podack, 1986, in Immunobiology of the Complement System, Academic Press; part (b) from J. Humphrey and R. Dourmashkin, 1969, Adv. Immunol. 11:75.]

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Responses

  • fatima
    What stabilizes the 3 pathways of complement?
    8 years ago
  • Rosalia Schultz
    What are the steps of the membrane attack pathway?
    8 years ago
  • Hamid Teodros
    What are the complement elements that get inserted intk the foreign cell?
    7 years ago
  • Markus
    Which complement factor do all threecomplement pathways converge?
    7 years ago

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