Title:Structure, Function and Control of Complement C5 and its Proteolytic Fragments
Volume: 12
Issue: 8
Author(s): N. S. Laursen, F. Magnani, R. H. Gottfredsen, S. V. Petersen and G. R. Andersen
Affiliation:
Keywords:
Anaphylatoxins, complement, immune evasion, innate immunity, pathogenesis, structural biology, infectious agent, opsonization, phagocytosis, immune complexes, apoptotic cells, zymogens, C-reactive protein, nucleophiles, lectin pathway.
Abstract: As part of the innate immune system, the complement system recognises a wide range of non-self
structures present on pathogens or altered self cells. Its activation elicits proteolytic cascades which eventually
results in the cleavage of the C5 protein into two fragments, C5a and C5b. The small anaphylatoxin C5a
induces a variety of biological responses upon binding to the 7TM receptors C5aR and the C5L2, while the
large C5b fragment nucleates formation of the membrane attack complex capable of killing susceptible
pathogens by the formation of a pore structure in association with complement components C6, C7, C8, and
C9. A number of regulatory molecules help to control C5 mediated immune responses towards host cells, but
in several major inflammatory conditions including sepsis and arthritis, C5a is believed to contribute
significantly to disease etiology. Inhibition of membrane attack complex assembly is already approved for
treatment of paroxysmal nocturnal haemoglobinuria and atypical hemolytic uremic syndrome. A number of
recent crystal structures have provided a comprehensive insight into the architecture and properties of intact
C5 and its fragments, and how pathogens interfere with their function. Here we review the functional and
structural aspects of C5 and its fragments, the pathological conditions associated with them, and strategies
employed by pathogens to interfere with the biological function of C5. Structural insight and elucidation of
evasion strategies employed by pathogens present a unique opportunity for promoting the development of
novel selective C5 inhibitors with therapeutic applications.
