Complement factor H

Complement factor H (fH) is a single chain plasma glycoprotein (approximately 150 kDa in size), with 20 domains termed complement control protein (CCP) domains or short consensus repeats (SCR). The complement factor H gene (CFH) is located on chromosome 1q32 in the regulators of complement activation (RCA) gene cluster, adjacent to the genes that code for the Complement factor H-Related Proteins (CFHRs). The RCA cluster includes additional regulators containing SCR domains, such as C4 Binding Protein (C4BP), Complement receptor type 1 (CR1), Complement decay-accelerating factor (DAF), Membrane cofactor protein (MCP). fH and C4BP are fluid-phase (soluble) complement regulators, while the remaining are membrane-bound and all these regulators share similarities in their structure and function. fH prevents the formation of the alternative pathway C3 (C3bBb) and C5 (C3bBb3b) convertases. This inhibitory effect is either by competition with Complement factor B (fB) for C3b binding, by convertase decay acceleration activity or by acting as a cofactor for the Complement factor I (fI)-mediated degradation of C3b. Important targets for fH binding, in the neighborhood of C3b on host cells, are glycosaminoglycans and sialic acid (polyanionic molecules), which increase the affinity of fH for C3b. In addition to C3b and polyanionic molecules, fH also interacts with various endogenous molecules, such as pentraxins, extracellular matrix (ECM) proteins, prion protein, adrenomedullin, DNA, annexin-II and histones, to inhibit complement activation on certain host surfaces such as glomerular basement membrane, the extracellular matrix, and late apoptotic cells. CFH gene mutations and polymorphisms, and auto-antibodies against fH adversely affect regulatory and target recognition functions of fH. Some of the diseases associated with fH dysfunction are atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD; also termed membranoproliferative glomerulonephritis (MPGN) type II) and age-related macular degeneration (AMD). Interestingly, microbes and multicellular pathogens can recruit host fH to their surface in order to protect themselves from complement attack

Complement C3

Complement C3 is the central component of the human complement system. It is ~186 kDa in size, consisting of an α-chain (~110 kDa) and a β-chain (~75 kDa) that are connected by cysteine bridges. C3 in its native form is inactive. Cleavage of C3 into C3b (~177 kDa) and C3a (~9 kDa) is a crucial step in the complement activation cascade, which can be initiated by one or more of the three distinct pathways, called alternative, classical and lectin complement pathways. In the alternative pathway, 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. A small percent of the resulting C3b is rapidly deposited (opsonization through covalent bond) in the immediate vicinity of the site of activation (e.g. pathogen surface) and now forms the major form of C3-convertase (C3bBb), thereby creating an efficient cycle of C3 cleavage. Properdin, a positive regulator of the alternative pathway convertases, provides a hub for the assembly of C3bBb in addition to stabilization of the convertase. Classical and lectin pathways, when activated with recognition of pathogens or immune complexes use another C3-convertase (C4b2a) to cleave C3 into C3a and C3b. Although the three pathways are activated independently, they converge at C3 and use C3 as a substrate for their pathway specific C3-convertase: C3(H20)Bb, C3bBb or C4b2a. Further, C3b undergoes successive proteolytic cleavages by the regulatory complement factor I (fI) in presence of cofactors and lead to generation of iC3b (~174 kDa), C3d/C3dg (~33 kDa), C3c (~142 kDa) and C3f (~2 kDa). C3a is an anaphylatoxin while C3b is involved in opsonization of pathogens or apoptotic cells. Covalently bound C3b on pathogen/apoptotic cell surface is recognized by host immune cells through phagocytic (or complement component) receptors and induce subsequent immune response or directly target pathogen for clearance. The C3a fragment functions as a chemokine, and thereby recruits phagocytic and granulocytic cells to the sites of inflammation and cause strong pro-inflammatory signaling through their G-protein coupled receptors (GPCRs). As pathogen or apoptotic cell surface bound C3-convertases (C3bBb or C4b2a) can induce the amplification of the alternative pathway, this pathway might contribute to the major part of the complement activation process, even when initially triggered by the classical pathway and/or lectin pathway. Continuous activation of complement pathways shifts the substrate preference from C3 to C5 by formation of C5-convertase (formed by addition of C3b fragment to C3-convertases, C3(H20)Bb3b, C3bBb3b and C4b2a3b). C5-convertase activates C5, which by series of additional steps, promotes killing of target cell (pathogen) by pore formation

MASP-2

UCSD Molecule Pages, volume 2, Issue

Complement C2

Complement C2 is a single chain serum glycoprotein (110 kDa), which serves as the catalytic subunit of C3 and C5 convertases in the classical and lectin pathways. During complement activation, C2 is cleaved by classical (C1s) or lectin (MBL-associated serine protease-2; MASP-2) proteases into two fragments: C2b and C2a. C2a, a serine protease, in complex with C4b fragment of complement factor C4, generates the C3 (C4b2a) or C5 (C4b2a3b) convertase. C3 convertase is very short-lived and cleaves complement C3 into C3a and C3b fragments (selective cleavage of Arg-|-Ser bond in C3 alpha-chain). C3 convertase requires the presence of magnesium and decays over time at physiologic temperatures. However, continuous activation of complement pathways shifts the substrate preference from C3 to C5 by formation of C5 convertase (formed by addition of C3b fragment to C3 convertase i.e. C4b2a3b). C5 convertase cleaves complement C5 to become activated into C5a and C5b fragments (selective cleavage of Arg-|-Xaa bond in C5 alpha-chain) and by a series of additional steps, promotes lysis of bacteria and damaged cells by pore or membrane attack complex (MAC) formation. Deficiency of C2 has been reported to be associated with certain autoimmune diseases. Single nucleotide polymorphisms (SNPs) in the C2 gene have been associated with altered susceptibility to age-related macular degeneration.Peer reviewedFinal Accepted Versio

Complement C3

Complement C3 is the central component of the human complement system. It is ~186 kDa in size, consisting of an α-chain (~110 kDa) and a β-chain (~75 kDa) that are connected by cysteine bridges. C3 in its native form is inactive. Cleavage of C3 into C3b (~177 kDa) and C3a (~9 kDa) is a crucial step in the complement activation cascade, which can be initiated by one or more of the three distinct pathways, called alternative, classical and lectin complement pathways. In the alternative pathway, 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. A small percent of the resulting C3b is rapidly deposited (opsonization through covalent bond) in the immediate vicinity of the site of activation (e.g. pathogen surface) and now forms the major form of C3-convertase (C3bBb), thereby creating an efficient cycle of C3 cleavage. Properdin, a positive regulator of the alternative pathway convertases, provides a hub for the assembly of C3bBb in addition to stabilization of the convertase. Classical and lectin pathways, when activated with recognition of pathogens or immune complexes use another C3-convertase (C4b2a) to cleave C3 into C3a and C3b. Although the three pathways are activated independently, they converge at C3 and use C3 as a substrate for their pathway specific C3-convertase: C3(H20)Bb, C3bBb or C4b2a. Further, C3b undergoes successive proteolytic cleavages by the regulatory complement factor I (fI) in presence of cofactors and lead to generation of iC3b (~174 kDa), C3d/C3dg (~33 kDa), C3c (~142 kDa) and C3f (~2 kDa). C3a is an anaphylatoxin while C3b is involved in opsonization of pathogens or apoptotic cells. Covalently bound C3b on pathogen/apoptotic cell surface is recognized by host immune cells through phagocytic (or complement component) receptors and induce subsequent immune response or directly target pathogen for clearance. The C3a fragment functions as a chemokine, and thereby recruits phagocytic and granulocytic cells to the sites of inflammation and cause strong pro-inflammatory signaling through their G-protein coupled receptors (GPCRs). As pathogen or apoptotic cell surface bound C3-convertases (C3bBb or C4b2a) can induce the amplification of the alternative pathway, this pathway might contribute to the major part of the complement activation process, even when initially triggered by the classical pathway and/or lectin pathway. Continuous activation of complement pathways shifts the substrate preference from C3 to C5 by formation of C5-convertase (formed by addition of C3b fragment to C3-convertases, C3(H20)Bb3b, C3bBb3b and C4b2a3b). C5-convertase activates C5, which by series of additional steps, promotes killing of target cell (pathogen) by pore formation

MAp44

MAp44 is a ~44 kDa alternate splice product of MASP1 and is mainly expressed in the heart. Mannose/mannan binding lectin (MBL) associated serine proteases, MASP-1 and MASP-3 are other products of MASP1. Similar to MASP-1 (isoform 1 of MASP1, which represents the longest transcript), MAp44 has a C1r/C1s/Uegf/bmp1 (CUB) domain, calcium-binding EGF-like domain and complement control protein (CCP) domains. However, it lacks the serine protease domain of MASP-1 and therefore cannot perform MASP-1's functions. MAp44 binds to multimeric pathogen receptors such asMBL and the three ficolins, and is believed to play a regulatory role in the lectin pathway of complement activation

L-Ficolin

L-ficolin is a serum lectin synthesized (as a ~37 kDa polypeptide) predominantly by the liver, and is one of the key molecules of the innate immune system. It has an amino (N)-terminal cysteine-rich region, a middle stretch of a collagen-like sequence, and a fibrinogen-like domain in the carboxy (C)-terminus. Three identical polypeptides form a structural (triple helical) subunit, with the help of the collagen-like domain. Further oligomerization of this subunit results in different sized L-ficolin molecules (from dimers to tetramers) in circulation. However, the tetrameric form (composed of 12 polypeptides) is the most prevalent structure. The polypeptides in the structural subunit are cross-linked by disulphide bonds in the N-terminal region. The fibrinogen-like domain forms a globular structure. The overall structure of oligomeric L-ficolin closely resembles mannose-binding lectin (MBL). Similar to MBL, L-ficolin also acts as a pattern recognition receptor. It primarily recognizes acetylated sugar residues on the cell surface of different gram-positive and gram-negative bacteria, viruses and other pathogens. There are two pathways by which L-ficolin may participate in a host defense response: 1) It activates the complement lectin pathway, via MBL/ficolin associated serine proteases (MASPs), that converges with the classical complement pathway at the level of complement C4, and 2) it may also act directly as an opsonin, enhancing phagocytosis by binding to cell-surface receptors present on phagocytic cells. M-ficolin and H-ficolin are structurally similar to L-ficolin. However, they differ in their tissue expression and binding affinities to pathogenic ligands

MASP-3

MASP-3 (mannose/mannan binding lectin (MBL) associated serine protease-3) is ~82 kDa protein generated through alternative splicing of the MASP1 gene. This gene also generates MASP-1 and MAp44 proteins. MASP-3 is bound to multimeric forms of pathogen receptors, such as MBL and the three ficolins. MASP-3 has two CUB, a calcium-binding EGF-like, a trypsin-like serine protease and two complement control protein (CCP) domains. The serine protease domain however, is not known to be active and does not act on substrates of either MASP-1 or MASP-2. Instead, it competes with MASP-1 and MASP-2 to bind to MBL and therefore plays a regulatory role in the lectin pathway of complement activation. In mice however, MASP-3 can activate the alternative complement pathway, by directly activating complement factor D (fD)

Complement factor H

Complement factor H (fH) is a single chain plasma glycoprotein (approximately 150 kDa in size), with 20 domains termed complement control protein (CCP) domains or short consensus repeats (SCR). The complement factor H gene (CFH) is located on chromosome 1q32 in the regulators of complement activation (RCA) gene cluster, adjacent to the genes that code for the Complement factor H-Related Proteins (CFHRs). The RCA cluster includes additional regulators containing SCR domains, such as C4 Binding Protein (C4BP), Complement receptor type 1 (CR1), Complement decay-accelerating factor (DAF), Membrane cofactor protein (MCP). fH and C4BP are fluid-phase (soluble) complement regulators, while the remaining are membrane-bound and all these regulators share similarities in their structure and function. fH prevents the formation of the alternative pathway C3 (C3bBb) and C5 (C3bBb3b) convertases. This inhibitory effect is either by competition with Complement factor B (fB) for C3b binding, by convertase decay acceleration activity or by acting as a cofactor for the Complement factor I (fI)-mediated degradation of C3b. Important targets for fH binding, in the neighborhood of C3b on host cells, are glycosaminoglycans and sialic acid (polyanionic molecules), which increase the affinity of fH for C3b. In addition to C3b and polyanionic molecules, fH also interacts with various endogenous molecules, such as pentraxins, extracellular matrix (ECM) proteins, prion protein, adrenomedullin, DNA, annexin-II and histones, to inhibit complement activation on certain host surfaces such as glomerular basement membrane, the extracellular matrix, and late apoptotic cells. CFH gene mutations and polymorphisms, and auto-antibodies against fH adversely affect regulatory and target recognition functions of fH. Some of the diseases associated with fH dysfunction are atypical hemolytic uremic syndrome (aHUS), dense deposit disease (DDD; also termed membranoproliferative glomerulonephritis (MPGN) type II) and age-related macular degeneration (AMD). Interestingly, microbes and multicellular pathogens can recruit host fH to their surface in order to protect themselves from complement attack

H-Ficolin

H-ficolin is a serum lectin synthesized (as a ~34 kDa polypeptide) predominantly by the liver and lung tissues and is one of the soluble pattern recognition receptors of the innate immune system. It is structurally similar to L- and M- ficolins, but is different in its tissue expression and binding affinities to pathogenic ligands. Ficolins have an amino (N)-terminal cysteine-rich region, a middle stretch of a collagen-like sequence, and a fibrinogen-like domain in the carboxy (C)-terminus. Three identical polypeptides form a structural (triple helical) subunit, with the help of the collagen-like domain. Further oligomerization of this subunit results in different sized H-ficolin molecules in circulation. The polypeptides in the structural subunit are cross-linked by disulphide bonds in the N-terminal region and the fibrinogen-like domain forms a globular structure. Thus, the overall structure of H-ficolin also resembles mannose/mannan- binding lectin (MBL). The primary role of H-ficolin is that of a pattern recognition receptor, recognizing acetylated sugar residues on the cell surface of different bacteria, viruses and other pathogens. There are two pathways by which H-ficolin may participate in a host defense response: 1) It activates the complement lectin pathway, via MBL/ficolin associated serine proteases (MASPs), that converges with the classical complement pathway at the level of complement C4, and 2) it may also act directly as an opsonin, enhancing phagocytosis by binding to cell-surface receptors present on phagocytic cells