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Complement activation and regulation #01
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
The complement system is a complex cascade of serum proteins. Three routes of recognition lead to activation of the complement system: the classical (antibody-mediated) pathway, the lectin pathway and the alternative pathway. All three pathways converge in the cleavage of C3 into its active fragments, C3a and C3b, by the C3 convertases. Complement activation is regulated through manipulation of the activity of several proteases. This network captures five proteases (nodes in yellow) in interplay with six substrates (nodes in green), four co-factors (nodes in light yellow: CD35, CD46, CD55, CD59), two inhibitors (nodes in red) and other binding proteins such as C4BP (c4bpa).
C4BP is a plasma protein involved in the regulation of the C3 convertase (C4b2a EC 3.4.21.43) of the classical complement pathway. It exerts its regulatory function by accelerating the dissociation of the catalytic subunit C2a from the C4bC2a complex, presumably by competing with C2a for its binding site on C4b. It binds multiple molecules of C4b and, by a mechanism that is poorly understood, converts the bound C4b into a substrate for the plasma serine protease factor I. C4BP also forms a specific one-to-one complex with vitamin K-dependent protein S using a binding site distinct from the multiple binding sites for C4b.
Protein S is one of the molecules involved in down-regulation of the coagulation process. It serves as a cofactor of activated protein C (APC, green) in the inactivation of activated FV (FVa) and FVIII (FVIIIa). It is also able to inhibit the activation of FX and prothrombin in an APC-independent manner. Protein S is susceptible to proteolysis by thrombin (node labeled f2), factor Xa (FXa) and elastase within the thrombin-sensitive region. Thrombin cleaves protein S at Arg49 and Arg70, with a preference for Arg49. Cleavage at Arg60 has also been reported but occurs only when the other two sites are unavailable.
In the alternative pathway, C3 convertase (C3bBb, EC 3.4.21.47) causes a gradual acceleration of C3b production, which plays a central role in the formation of the C5 convertase (C3bC3bBb). The C3b component is proteolysed by factor I, a serine protease (EC 3.4.21.45). Both dissociation and proteolysis are mediated by regulatory proteins through their decay acceleration and factor I cofactor activities.
The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases. Complement activation may be controlled at many different steps. A great deal of attention has focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a, as these generate the inflammatory peptides C3a and C5a.
C4BP is a plasma protein involved in the regulation of the C3 convertase (C4b2a EC 3.4.21.43) of the classical complement pathway. It exerts its regulatory function by accelerating the dissociation of the catalytic subunit C2a from the C4bC2a complex, presumably by competing with C2a for its binding site on C4b. It binds multiple molecules of C4b and, by a mechanism that is poorly understood, converts the bound C4b into a substrate for the plasma serine protease factor I. C4BP also forms a specific one-to-one complex with vitamin K-dependent protein S using a binding site distinct from the multiple binding sites for C4b.
Protein S is one of the molecules involved in down-regulation of the coagulation process. It serves as a cofactor of activated protein C (APC, green) in the inactivation of activated FV (FVa) and FVIII (FVIIIa). It is also able to inhibit the activation of FX and prothrombin in an APC-independent manner. Protein S is susceptible to proteolysis by thrombin (node labeled f2), factor Xa (FXa) and elastase within the thrombin-sensitive region. Thrombin cleaves protein S at Arg49 and Arg70, with a preference for Arg49. Cleavage at Arg60 has also been reported but occurs only when the other two sites are unavailable.
In the alternative pathway, C3 convertase (C3bBb, EC 3.4.21.47) causes a gradual acceleration of C3b production, which plays a central role in the formation of the C5 convertase (C3bC3bBb). The C3b component is proteolysed by factor I, a serine protease (EC 3.4.21.45). Both dissociation and proteolysis are mediated by regulatory proteins through their decay acceleration and factor I cofactor activities.
The human complement system is an important component of innate immunity. Complement-derived products mediate functions contributing to pathogen killing and elimination. However, inappropriate activation of the system contributes to the pathogenesis of immunological and inflammatory diseases. Complement activation may be controlled at many different steps. A great deal of attention has focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a, as these generate the inflammatory peptides C3a and C5a.
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