Complement system (Homo sapiens)

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The complement activation takes place through one or more of the well-established (alternative, classical or lectin) pathways consisting of plasma and membrane-bound proteins. All three pathways converge at the level of complement C3 [1] and are controlled by regulators [2]. Complement C3 belongs to the alpha-2-macroglobulin family of proteins, and consists of a alpha-chain and an beta-chain. Cleavage of C3 which can be initiated by one or more of the above three distinct pathways, into C3b[Proteolysis@23-667,749-1663] and C3a [Proteolysis@672-748] is an important step in the complement activation cascade. Classical and lectin pathways, when activated with recognition of pathogens (or immune complexes) use C3-convertase [C4b2a] to cleave complement C3 into C3a and C3b [3]. However, in alternative pathway a small fraction of the C3 molecules are hydrolyzed to C3(H20) exposing new binding sites. This hydrated C3 [C3(H20)] recruits complement factor B [fB], which is then cleaved by complement factor D [fD] to result in formation of the minor form of C3-convertase [C3(H20)Bb] that cleaves C3 into C3a and C3b [4]. Further, addition of C3b to C3 convertase [C3bBb or C4b2a] results in C5 convertase [C3bBb3b or C4b2a3b], that cleaves complement C5 to C5a and C5b, is the last enzymatic step of the complement activation cascade [5][6]. During complement activation C5b interacts with complement C6, C7, C8 and C9 in a sequential and non-catalyzed manner to result in the formation of Terminal Complement Complex (TCC) [7]. The entire network is considered as a simple recognition and elimination system of host-immune complexes and apoptotic and/or pathogens, and therefore promotes host immune homeostasis. The complement system is also involved in cross-talk with other processes related to coagulation, lipid metabolism and cancer. However, many pathogens counteract complement attack through a range of different mechanisms, such acquisition of host complement regulators to the surface of pathogen, or secretion of complement inactivation factors. In order to have a holistic view of the entire complement network, Dr. John D.Lambris group (University of Pennsylvania) developed the Complement Map Database (CMAP) which is a unique repository focused on documented molecular interactions described within the complement cascade and between complement and other biological systems. Information contained in CMAP (http://www.complement.us/cmap/index.php)[8] is entirely based on published experimental data and is fully revised by experts in the field. Further, the Signaling Gateway Molecule Pages -SGMP-( https://escholarship.org/uc/molecule_pages)[9] has published a curated data on each protein involved in human complement activation pathways (refs. [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] ).