|Active Form||Function of the Active Form|
|C1Q||Binding directly to pathogen surfaces or indirectly to antibody bound to pathogens, thus allowing autoactivation of C1R.|
|C1R||Cleaves C1S to active protease.|
|C1S||Cleaves C4 and C2.|
The classical pathway plays a role in both innate and adaptive immunity. Complement component C1q, the first component of this pathway, links the adaptive humoral immune response to the complement system by binding to antibodies complexed with antigens. C1q can, however, also bind directly to the surface of certain pathogens and thus trigger complement activation in the absence of antibody. C1q is part of the C1 complex, which comprises a single C1q molecule bound to two molecules each of the zymogens C1r and C1s. Complement component C1q is a calcium-dependent sugar-binding protein, a lectin, belonging to the collectin family of proteins, which contains both collagen-like and lectin domains hence the name collectin. It has six globular heads, linked together by a collagen-like tail, which surround the (C1r:C1s)2 complex. Binding of more than one of the C1q heads to a pathogen surface causes a conformational change in the (C1r:C1s)2 complex, which leads to activation of an autocatalytic enzymatic activity in C1r; the active form of C1r then cleaves its associated C1s to generate an active serine protease.
Once activated, the C1s enzyme acts on the next two components of the classical pathway, cleaving C4 and then C2 to generate two large fragments, C4b and C2b, which together form the C3 convertase of the classical pathway. In the first step, C1s cleaves C4 to produce C4b, which binds covalently to the surface of the pathogen. The covalently attached C4b then binds one molecule of C2, making it susceptible, in turn, to cleavage by C1s. C1s cleaves C2 to produce the large fragment C2b, which is itself a serine protease. The complex of C4b with the active serine protease C2b remains on the surface of the pathogen as the C3 convertase of the classical pathway. Its most important activity is to cleave large numbers of C3 molecules to produce C3b molecules that coat the pathogen surface. At the same time, the other cleavage product, C3a, initiates a local inflammatory response. These reactions comprise the classical pathway of complement activation.
The beneficial aspects of a moderately activated complement system include immune surveillance, removal of cellular debris, organ regeneration and neuroprotection. The two anaphylatoxins complement component 3a (C3a) and C5a have a role during organ regeneration, in neuroprotection - including in migration of neurons and synapse elimination - and in the release of progenitor haematopoietic stem cells. In addition, crosstalk and cooperative effects between C3a receptor (C3aR), C5aR, C5a receptor-like 2 (C5L2) and Toll-like receptors have been reported. These additional physiological functions highlight the role of complement in physiology and homeostasis and demonstrate that appropriate regulation and balanced or targeted activation are crucial to keep the complement system in its proper physiological state.
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