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Mechanism of complement cytolysis and the concept of channel-forming proteins
Insights
Complement forms membrane attack complexes (MACs) that create pores in cell membranes. Other proteins, like bacterial toxins, also form channels through self-association and a hydrophilic-to-amphiphilic transition.
Area of Science:
- Immunology
- Molecular Biology
- Biophysics
Background:
- The complement system generates membrane-bound C5b-9(m) complexes, crucial for cell membrane damage.
- These complexes form transmembrane pores, acting as primary lesions in target cells.
Purpose of the Study:
- To elucidate the mechanism of complement-mediated membrane damage.
- To draw analogies between complement C5b-9(m) complex formation and membrane-damaging bacterial toxins.
Main Methods:
- Analysis of the terminal complement reaction sequence.
- Morphological characterization of C5b-9(m) complexes.
- Comparative analysis of protein-mediated membrane channel formation.
Main Results:
- Complement C5b-9(m) complexes, with varying C9 numbers, form hollow protein channels.
- These channels create aqueous transmembrane pores in lipid bilayers.
- Analogies were found between C5b-9(m) and bacterial toxins like Staphylococcus aureus alpha-toxin and streptolysin-O.
Conclusions:
- Complement-induced membrane damage involves the formation of protein channels.
- Self-association and a hydrophilic-to-amphiphilic transition are common mechanisms for membrane-damaging proteins.
Abstract:
Complement damages membranes via the terminal reaction sequence that leads to the formation of membrane-bound, macromolecular C5b-9(m) protein complexes. These complexes represent C5b-8 monomers to which varying numbers of C9 molecules can be bound. Complexes carrying high numbers of C9 (ca. 6/8-12/16?) exhibit the morphology of hollow protein channels. Because they are embedded within the lipid bilayer, aqueous transmembrane pores are generated that represent the primary lesions caused by complement in the target cell membrane. Many other proteins damage membranes by forming channels in a manner analogous to the C5b-9(m) complex. Two prototypes of bacterial exotoxins, Staphylococcus aureus alpha-toxin and streptolysin-O, are discussed in this context, and attention is drawn to the numerous analogies existing among these protein systems. Common to all is the process of self-association of the native proteins to form supramolecular complexes. This event is in turn accompanied by a unique transition of the molecules from a hydrophilic to an amphiphilic state.