Complement cascade (Homo sapiens)

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<Pathway xmlns="http://genmapp.org/GPML/2010a" Name="Complement cascade" Organism="Homo sapiens" Data-Source="Reactome - http://www.reactome.org" Version="release 35" Author="de Bono, B" Maintainer="Jupe, S" Email="sjupe@ebi.ac.uk">
  <Comment Source="WikiPathways-description">The complement system is a biochemical cascade, so named because it 'complements' the ability of antibodies to clear pathogens. It is part of the innate immune system. Complement system proteins circulate in the blood as inactive precursors (pro-proteins). When triggered by the presence of microbes, complement proteases cleave complement proteins, initiating a cascade of further cleavages. The end-result of this activation is the activation of the membrane attack complex and cell lysis. The C3 and C5 components also lead to phagocytosis by leukocytes.

There are three branches that lead to activation of the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway.  Complement proteins are always present in the blood and a small percentage spontaneously activates. Innapropriate activation lead to damage to host cells, so the activation process is tightly controlled by several regulatory mechanisms.</Comment>
  <Comment Source="WikiPathways-category">Cellular Process</Comment>
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  <BiopaxRef>lit_173684</BiopaxRef>
  <BiopaxRef>lit_173730</BiopaxRef>
  <BiopaxRef>lit_174537</BiopaxRef>
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  <DataNode GraphId="n5_REACTOME_166718" TextLabel="Bacterial mannose-&#10;based carbohydrate &#10;surface pattern&#10;" Type="Unknown">
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  <DataNode GraphId="n6_REACTOME_166710" TextLabel="MBL-II:MASP-2 dimer:&#10;MASP-1 dimer &#10;complex&#10;" Type="Complex">
    <BiopaxRef>lit_166697</BiopaxRef>
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  <DataNode GraphId="n7_REACTOME_166719" TextLabel="MBL bound to &#10;mannose-based &#10;carbohydrates on &#10;bacterial surfaces&#10;" Type="Complex">
    <BiopaxRef>lit_166709</BiopaxRef>
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    <BiopaxRef>lit_166709</BiopaxRef>
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  <DataNode GraphId="n12_REACTOME_173582" TextLabel="Antigen: antibody: C1 &#10;complex&#10;" Type="Complex">
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  <DataNode GraphId="n13_REACTOME_173619" TextLabel="Antigen: antibody: C1 &#10;(activated C1R) &#10;complex&#10;" Type="Complex">
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  <DataNode GraphId="n23_REACTOME_166763" TextLabel="C4 activator&#10;" Type="Unknown">
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  <DataNode GraphId="n25_REACTOME_166778" TextLabel="Complement factor 2&#10;" Type="Protein">
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  <DataNode GraphId="n32_REACTOME_166822" TextLabel="Complement factor &#10;3&#10;" Type="Complex">
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  <DataNode GraphId="n33_REACTOME_109276" TextLabel="H2O&#10;" Type="Metabolite">
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  <DataNode GraphId="n36_REACTOME_173738" TextLabel="Complement Factor B&#10;" Type="Protein">
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    <Comment Source="WikiPathways-description">Linked by disulphide bond between positions 559 and 816.</Comment>
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    <Comment Source="WikiPathways-description">This entity is intended to represent any molecule that might be at the outer cell surface of any cell, host or microbial.</Comment>
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    <Comment Source="WikiPathways-description">Extracellular MBL oligomer complexed with MASP2 binds to a repetitive carbohydrate motif on a target surface to form a MASP2:MBL oligomer:carbohydrate complex on the surface. Such motifs occur on the surfaces of viruses, bacteria, fungi and protozoa. The affinity of any one MBL binding site for a carbohydrate ligand is low, but interaction between multiple binding sites on an MBL oligomer and a repetitive carbohydrate motif on a target surface allow high-avidity binding. The specificity of the MBL binding site (it does not bind glucose or sialic acid) and the requirement for a repeated target motif may account for the failure of MBL to bind human glycoproteins under normal conditions (Petersen et al. 2001). This reaction in particular represents the interaction of MBL with bacterial mannose repeats.</Comment>
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    <Comment Source="WikiPathways-description">In this reaction, the MASP2 serine protease moiety of an MBL oligomer:MASP2 complex bound to a target surface becomes catalytically active.</Comment>
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    <Comment Source="WikiPathways-description">C1 activation requires interaction with two separate Fc domains, so pentavalent IgM antibody is far more efficient at complement activation than IgG antibody (Muller-Eberhard and Kunkel 1961). Antibody binding results in a conformational change in the C1r component of the C1 complex and a proteolytic cleavage of C1r, activating it (Ziccardi and Cooper 1976). This reaction is irreversible under physiological conditions.</Comment>
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    <Comment Source="WikiPathways-description">In this irreversible reaction, the activated C1r subunit of the C1:antibody:antigen complex cleaves the C1s subunit of the complex, activating it in turn (Ziccardi and Cooper 1976).</Comment>
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    <Comment Source="WikiPathways-description">The alpha chain of C4 is cleaved, releasing an N-terminal portion of this chain as C4a. The beta and gamma chains are not cleaved and remain linked to the alpha chain by disulfide bonds (Nagasawa et al. 1976, 1980). The resulting C4b heterotrimer undergoes a gross conformational change; the internal thioester in C4b becomes exposed and able to form covalent bonds with surrounding molecules (Law and Dodds 1997). A large proportion of the bonds formed are with water, but some will attach C4b to biological surfaces (Rother et al. 1998). This irreversible reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Fujita et al. 2004; Hajela et al. 2002), and by activated C1, generated through the classical pathway (Muller-Eberhard and Lepow 1965).&lt;br&gt;&lt;br&gt;N.B. Humans have two highly polymorphic loci for Complement factor 4, C4A and C4B. C4A alleles carry the Rodgers (Rg) blood group antigens while the C4B alleles carry the Chido (Ch) blood group antigens. The two loci encode non identical C4 peptides; C4 derived from C4A reacts more rapidly with the amino groups of peptide antigens while C4B allotypes react more rapidly with the hydroxyl group of carbohydrate antigens. The names of the two loci are always represented in uppercase. C4a and C4b refer to the peptide products of Complement Factor 4 cleavage.</Comment>
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    <Comment Source="WikiPathways-description">C2 is cleaved into the large C2a and the small C2b fragment. This irreversible, extracellular reaction can be catalyzed by activated MBL, generated through the lectin pathway of complement activation (Vorup-Jensen et al. 2000), and by activated C1, generated through the classical pathway (Nasagawa and Stroud 1977). N.B. Early literature refers to the larger fragment of C2 as C2a. However, complement scientists decided that the smaller of all C fragments should be designated with an 'a', the larger with a 'b', changing the nomenclature for C2. For this reason recent literature may refer to the larger C2 fragment as C2b, and the classical C3 convertase as C4bC2b. Throughout this pathway, Reactome uses the current (Oct 2010) Uniprot names which adhere to the original naming practice.</Comment>
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    <Comment Source="WikiPathways-description">C4b and C2a form a complex termed the classical pathway C3 convertase (Muller-Eberhard et al. 1967). C2a that fails to bind C4b is rapidly inactivated.</Comment>
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    <Comment Source="WikiPathways-description">The thioester linkage between cysteine residue 1010 and glutamine residue 1013 in the alpha chain of Complement factor 3 (C3) can spontaneously hydrolyze, yielding so-called C3(H2O) (Tack et al. 1980; Pangburn &amp; Muller-Eberhard 1980; Pangburn et al. 1981). Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B. The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn &amp; Muller-Eberhard 1983). If not bound by Factor B, C3(H2O) binds Factor H and is inactivated by Factor I</Comment>
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    <Comment Source="WikiPathways-description">Thioester bond hydrolysis causes conformational rearrangements that give C3(H2O) the ability to bind Factor B (Schreiber et al. 1978). The spontaneous hydrolysis rate of C3 under physiological conditions and temperature is about l% per hour, thus the C3b-like properties of C3(H2O) provide a continuous low level initiation of the alternative pathway of complement activation (Pangburn &amp; Muller-Eberhard 1983).</Comment>
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    <Comment Source="WikiPathways-description">Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the soluble C3(H2O):Factor B complex, yielding C3(H2O):Factor Bb and an inactive polypeptide, Factor Ba (Fearon and Austin 1975; Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978).</Comment>
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    <Comment Source="WikiPathways-description">C3b:Bb is naturally labile with a half-life of ~90 s; association of the complex with properdin extends the half-life to ~30 min. (Medicus et al. 1976). Properdin is found in the blood as a mixture of multivalent oligomers: 30% dimers, 45% trimers, 10% tetramers, and 15% higher oligomers. Monomers associate with one another in a head-to-tail arrangement, producing closed circular structures (Smith et al. 1984). These features suggest that the properdin oligomer associated with a C3b:Bb complex on a surface such as a cell membrane can facilitate recruitment of additional C3b:Bb complexes to the site (Farries et al. 1988; Hourcade 2006).</Comment>
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    <Comment Source="WikiPathways-description">The complex of C3b:Factor Bb, stabilized on the cell surface by properdin, catalyzes the cleavage of C3 to yield C3b and C3a. The C3b is recruited to the C3b:Factor B complex through its interaction with properdin (Daha et al. 1976; Medicus et al. 1976; Hourcade 2006), yielding the alternate C5 convertase.</Comment>
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    <Comment Source="WikiPathways-description">C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), C3b and the Bb fragment of Factor B form the alternative pathway C3 convertase. The C3(H2O):Bb C3 convertase is sometimes called the initiating convertase, and the C5 convertases also have C3 convertase activity (Rawal &amp; Pangburn 2001).</Comment>
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    <Comment Source="WikiPathways-description">C3(H2O):Factor Bb is a C3 convertase, sometimes referred to as the initial C3 convertase (iC3). The Factor Bb component catalyzes the hydrolysis of C3 to produce C3b and C3a. This reaction is not known to be directly coupled to the association of C3b complexes with a cell surface. It is believed that a small proportion of C3b spontaneously associates with the cell surface, otherwise it is rapidly inactivated (Muller-Eberhard 1988).</Comment>
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    <Comment Source="WikiPathways-description">Factor D, a constitutively active serine protease found in trace amounts in the blood, cleaves a specific Arg-Lys bond in the Factor B component of the cell surface-associated C3b:Factor B complex, yielding the alternate C3 convertase C3bBb on the surface and releasing an inactive polypeptide, Factor Ba (Lesavre and Muller-Eberhard 1978; Lesavre et al. 1979; Schreiber et al. 1978).</Comment>
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    <Comment Source="WikiPathways-description">C5 convertases are serine proteases that cleave C5 with high efficiency; the C3 convertases can cleave C5 but have a poor affinity for C5, with a Km of 6-9 microM. The high affinity C5 convertases are generated when the low affinity C3/C5 convertases such as C4b:C2a deposit C3b by cleaving native C3. These C3b-containing C3/C5 convertases have Km values of 0.005 microM, well below the normal concentration of C5 in blood (0.37 microM). They have very low Vmax rates, just one C5 cleaved per 1â4 min per enzyme (Rawal &amp; Pangburn 1998).</Comment>
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    <Comment Source="WikiPathways-description">The cleavage of C4 into C4a and C4b releases an acyl group from the intrachain thioester bond, allowing C4b to bond covalently to any adjacent biological substrates (Dodds &amp; Law 1998). C4 is encoded at two loci, C4A and C4B. The C4b proteins derived from these genes are not identical and have different binding preferences (Law et al 1984, Sepp et al. 1993); C4A-derived C4b binds more efficiently than C4B-derived C4b to amino groups, while C4B-derived C4b is more effective than C4A in binding to hydroxyl groups. The site of C4b deposition is not clearly established (MÃ¸ller-Kristensen et al. 2003) but generally accepted to be the activating cell membrane surface, though it may be the activating complex itself.</Comment>
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</Pathway>