Search results for C4B

Showing 27 results out of 69

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Protein (5 results from a total of 14)

Identifier: R-HSA-981710
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: C4B: P0C0L5
Identifier: R-HSA-2855052
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: C4B: P0C0L5
Identifier: R-HSA-981720
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: P0C0L5
Identifier: R-HSA-981698
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: P0C0L5
Identifier: R-HSA-981708
Species: Homo sapiens
Compartment: extracellular region
Primary external reference: UniProt: P0C0L5

Set (5 results from a total of 7)

C4b

Identifier: R-HSA-981700
Species: Homo sapiens
Compartment: extracellular region

C4b

Identifier: R-HSA-3266541
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-2855046
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-977357
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-981661
Species: Homo sapiens
Compartment: plasma membrane

Complex (5 results from a total of 16)

Identifier: R-HSA-2855048
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-2855050
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-9638168
Species: Homo sapiens
Compartment: extracellular region
Identifier: R-HSA-981675
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-981639
Species: Homo sapiens
Compartment: plasma membrane

Reaction (5 results from a total of 25)

Identifier: R-HSA-977626
Species: Homo sapiens
Compartment: plasma membrane, extracellular region
The most abundant form of C4b-binding protein (C4BP) consists of seven alpha-chains (70kDa) and one beta-chain (45kDa) all linked by disulphide bonds to form a native protein with a molecular weight of 570kDa (Hilarp et al. 1989). Each alpha chain can bind C4b; it is not known whether full occupancy is necessary for subsequent events. The beta chain binds and inactivates Protein S, a component of the coagulation system. C4BP down-regulates complement activity in several ways: It binds to C4b thus inhibiting the formation of the classical pathway C3 convertase C4bC2a; it acts as a decay accelerating factor for existing convertases, probably by promoting dissociation of C2a; it is a cofactor in Factor I mediated C4b proteolysis.
Identifier: R-HSA-8951486
Species: Homo sapiens
Compartment: plasma membrane
Membrane cofactor protein (MCP; CD46) is a widely distributed cell surface glycoprotein that can bind C3b and C4b, which are cofactors for Complement factor I.
Identifier: R-HSA-981713
Species: Homo sapiens
Compartment: plasma membrane, extracellular region
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 & 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 (Møller-Kristensen et al. 2003) but generally accepted to be the activating cell membrane surface, though it may be the activating complex itself.
Identifier: R-HSA-2855047
Species: Homo sapiens
Compartment: extracellular region
Cleavage of C4 exposes a highly reactive thioester bond on the C4b molecule. The thioester bond is rapidly inactivated by hydrolysis if C4b does not bind to the target cell surface [Sepp A et al 1993].
Identifier: R-HSA-166753
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
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).

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.

Pathway (4 results from a total of 4)

Identifier: R-HSA-166786
Species: Homo sapiens
Two pathways lead to a complex capable of activating C4 and C2.

The classical pathway is triggered by activation of the C1-complex, which consists of hexameric molecule C1q and a tetramer comprising two C1r and two C1s serine proteinases. This occurs when C1q binds to IgM or IgG complexed with antigens, a single IgM can initiate the pathway while multiple IgGs are needed, or when C1q binds directly to the surface of the pathogen. Binding leads to conformational changes in C1q, activating the serine protease activity of C1r, which then cleaves C1s, another serine protease. The C1r:C1s component is now capable of splitting C4 and C2 to produce the classical C3-convertase C4b2a. C1r and C1s are additionally controlled by C1-inhibitor.(Kerr MA 1980)
The lectin pathway is similar in operation but has different components.

Mannose-binding lectin (MBL) or ficolins (L-ficolin, M-ficolin and H-ficolin) initiate the lectin pathway cascade by binding to specific carbohydrate patterns on pathogenic cell surfaces. MBL and ficolins circulate in plasma in complexes with homodimers of MBL-associated serine proteases (MASP) (Fujita et al. 2004; Hajela et al. 2002). Upon binding of human lectin (MBL or ficolins) to the target surface the complex of lectin:MASP undergoes conformational changes, which results in the activation of MASPs by cleavage (Matsushita M et al. 2000; Fujita et al. 2004). Activated MASPs become capable of C4 and C2 cleavage, giving rise to the same C3 convertase C4b:C2a as the classical pathway.

Identifier: R-HSA-977606
Species: Homo sapiens
Compartment: plasma membrane, extracellular region
Two inherent features of complement activation make its regulation very important:
1. There is an inherent positive feedback loop because the product of C3 activation forms part of an enzyme that causes more C3 activation.
2. There is continuous low-level activation of the alternative pathway (see Spontaneous hydrolysis of C3 thioester).

Complement cascade activation is regulated by a family of related proteins termed the regulators of complement activation (RCA). These are expressed on healthy host cells. Most pathogens do not express RCA proteins on their surface, but many have found ways to evade the complement system by stably binding the RCA that circulates in human plasma (Lambris et al. 2008); trapping RCA is by far the most widely employed strategy for avoiding the complement response. RCA recruitment is common in bacteria such as E. coli and streptococci (Kraiczy & Wurzner 2006) and has also been described for viruses, fungi and parasites. RCA deposition and the complement system also have an important role in tissue homeostasis, clearing dead cells and debris, and preventing damage from oxidative stress (Weismann et al. 2011).

RCA proteins control complement activation in two different ways; by promoting the irreversible dissociation (decay acceleration) of complement convertases and by acting as cofactors for Complement factor I (CFI)-mediated cleavage of C3b and C4b.
Decay accelerating factor (DAF, CD55), Complement factor H (FH), Membrane Cofactor Protein (MCP) and Complement receptor 1 (CR1) are composed of arrays of tandem globular domains termed CCPs (complement control protein repeats) or SCRs (short consensus repeats). CR1, MCP and FH are cofactors for the CFI-mediated cleavage of C3b, generating iC3b. CR1 and MCP are also cofactors for C4b cleavage.
C4BP is an additional cofactor for the CFI-mediated cleavage of C4b.
Identifier: R-HSA-166662
Species: Homo sapiens
Activation of the lectin pathway (LP) is initiated by Mannose-binding lectin (MBL), the hetero-complex CL-LK formed from COLEC11 (Collectin liver 1, CL-L1) and COLEC10 (Collectin kidney 1, CL-K1), and the ficolins (FCN1, FCN2, FCN3). All are Ca-dependent (C-type) lectins that initiate the complement cascade after binding to specific carbohydrate patterns on the target cell surface. All form trimers and larger oligomers (Jensen et al. 2005, Dommett et al. 2006, Garlatti et al. 2010). MBL and ficolins circulate in plasma as complexes with homodimers of MBL-associated serine proteases (MASP) (Fujita et al. 2004, Hajela et al. 2002). MASP1, MASP2 and MASP3 have all been reported to mediate complement activation. Upon binding of human lectin to the target surface, the complex of lectin:MASP undergoes conformational changes that result in MASP cleavage and activation (Matsushita M et al. 2000, Fujita et al. 2004). Active MASP2 cleaves C4 to generate C4a and C4b. C4b binds to the target cell surface via its thioester bond, then binds circulating C2 (Law and Dodds 1997). Bound C2 is cleaved by MASP2 to yield the C3 convertase C4b:C2a. The active form of MASP1 was reported to cleave C2 in a manner similar to MASP2 (Matsushita et al. 2000, Chen & Wallis 2004). MASP1 can cleave proenzyme MASP2, leading to complement activation (Heja et al. 2012). MASP1 can also cleave fibrinogen to yield fibrinopeptide B, and activates factor XIII. MASP1 may have a role in removal of 'dead C3', i.e. C3(H2O) (Hajela et al. 2002). In addition to MASP1 to 3, two alternatively-slpiced forms of MASP1 (MAp44) and MASP2 (sMAP) have been implicated in complement cascade signaling (Takahashi et al. 1999, Degn et al. 2010). The functions of MASP3, sMAP and MAp44 in the lectin pathway remain to be clarified.
Identifier: R-HSA-166658
Species: Homo sapiens
Compartment: extracellular region, plasma membrane
In the complement cascade, a panel of soluble molecules rapidly and effectively senses a danger or damage and triggers reactions to provide a response that discriminates among foreign intruders, cellular debris, healthy and altered host cells (Ricklin D et al. 2010). Complement proteins circulate in the blood stream in functionally inactive states. When triggered the complement cascade generates enzymatically active molecules (such as C3/C5 convertases) and biological effectors: opsonins (C3b, C3d and C4b), anaphylatoxins (C3a and C5a), and C5b, which initiates assembly of the lytic membrane attack complex (MAC). Three branches lead to complement activation: the classical, lectin and alternative pathways (Kang YH et al. 2009; Ricklin D et al. 2010). The classical pathway is initiated by C1 complex binding to immune complexes, pentraxins or other targets such as apoptotic cells leading to cleavage of C4 and C2 components and formation of the classical C3 convertase, C4bC2a. The lectin pathway is activated by binding of mannan-binding lectin (MBL) to repetitive carbohydrate residues, or by binding of ficolins to carbohydrate or acetylated groups on target surfaces. MBL and ficolins interact with MBL-associated serine proteases (MASP) leading to cleavage of C4 and C2 and formation of the classical C3 convertase, C4bC2a. The alternative pathway is spontaneously activated by the hydrolysis of the internal thioester group of C3 to give C3(H2O). Alternative pathway activation involves interaction of C3(H2O) and/or previously generated C3b with factor B, which is cleaved by factor D to generate the alternative C3 convertases C3(H2O)Bb and/or C3bBb. All three pathways merge at the proteolytic cleavage of component C3 by C3 convertases to form opsonin C3b and anaphylatoxin C3a. C3b covalently binds to glycoproteins scattered across the target cell surface. This is followed by an amplification reaction that generates additional C3 convertases and deposits more C3b at the local site. C3b can also bind to C3 convertases switching them to C5 convertases, which mediate C5 cleavage leading to MAC formation. Thus, the activation of the complement system leads to several important outcomes: opsonization of target cells to enhance phagocytosis, lysis of target cells via membrane attack complex (MAC) assembly on the cell surface, production of anaphylatoxins C3a/C5a involved in the host inflammatory response, C5a-mediated leukocyte chemotaxis, and clearance of antibody-antigen complexes. The complement system is able to distinguish between pathological and physiological challenges, i.e. the outcomes of complement activation are predetermined by the trigger and are tightly tuned by a combination of initiation events with several regulatory mechanisms. These regulatory mechanisms use soluble (e.g., C4BP, CFI and CFH) and membrane-bound regulators (e.g., CR1, CD46(MCP), CD55(DAF) and CD59) and are coordinated by complement receptors such as CR1, CR2, etc. In response to microbial infection complement activation results in flagging microorganisms with opsonins for facilitated phagocytosis, formation of MAC on cells such as Gram-negative bacteria leading to cell lysis, and release of C3a and C5a to stimulate downstream immune responses and to attract leukocytes. Most pathogens can be eliminated by these complement-mediated host responses, though some pathogenic microorganisms have developed ways of avoiding complement recognition or blocking host complement attack resulting in greater virulence (Lambris JD et al. 2008; Serruto D et al. 2010). All three complement pathways (classical, lectin and alternative) have been implicated in clearance of dying cells (Mevorach D et al. 1998; Ogden CA et al. 2001; Gullstrand B et al.2009; Kemper C et al. 2008). Altered surfaces of apoptotic cells are recognized by complement proteins leading to opsonization and subsequent phagocytosis. In contrast to pathogens, apoptotic cells are believed to induce only a limited complement activation by allowing opsonization of altered surfaces but restricting the terminal pathway of MAC formation (Gershov D et al. 2000; Braunschweig A and Jozsi M 2011). Thus, opsonization facilitates clearance of dying cells and cell debris without triggering danger signals and further inflammatory responses (Fraser DA et al. 2007, 2009; Benoit ME et al. 2012). C1q-mediated complement activation by apoptotic cells has been shown in a variety of human cells: keratinocytes, human umbilical vein endothelial cells (HUVEC), Jurkat T lymphoblastoid cells, lung adenocarcinoma cells (Korb LC and Ahearn JM 1997; Mold C and Morris CA 2001; Navratil JS et al. 2001; Nauta AJ et al. 2004). In addition to C1q the opsonization of apoptotic Jurkat T cells with MBL also facilitated clearance of these cells by both dendritic cells (DC) and macrophages (Nauta AJ et al. 2004). Also C3b, iC3b and C4b deposition on apoptotic cells as a consequence of activation of the complement cascade may promote complement-mediated phagocytosis. C1q, MBL and cleavage fragments of C3/C4 can bind to several receptors expressed on macrophages (e.g. cC1qR (calreticulin), CR1, CR3, CR4) suggesting a potential clearance mechanism through this interaction (Mevorach D et al. 1998; Ogden CA et al. 2001). Apoptosis is also associated with an altered expression of complement regulators on the surface of apoptotic cells. CD46 (MCP) bound to the plasma membrane of a healthy cell protects it from complement-mediated attack by preventing deposition of C3b and C4b, and reduced expression of CD46 on dying cells may lead to enhanced opsonization (Elward K et al. 2005). Upregulation of CD55 (DAF) and CD59 on apoptotic cell surfaces may protect damaged cells against complement mediated lysis (Pedersen ED et al. 2007; Iborra A et al. 2003; Hensel F et al. 2001). In addition, fluid-phase complement regulators such as C4BP, CFH may also inhibit lysis of apoptotic cells by limiting complement activation (Trouw LA et al 2007; Braunschweig A and Jozsi M. 2011). Complement facilitates the clearance of immune complexes (IC) from the circulation (Chevalier J and Kazatchkine MD 1989; Nielsen CH et al. 1997). Erythrocytes bear clusters of complement receptor 1 (CR1 or CD35), which serves as an immune adherence receptor for C3 and/or C4 fragments deposited on IC that are shuttled to liver and spleen, where IC are transferred and processed by tissue macrophages through an Fc receptor-mediated process. Complement proteins are always present in the blood and a small percentage spontaneously activate. Inappropriate activation leads to host cell damage, so on healthy human cells any complement activation or amplification is strictly regulated by surface-bound regulators that accelerate decay of the convertases (CR1, CD55), act as a cofactor for the factor I (CFI)-mediated degradation of C3b and C4b (CR1, CD46), or prevent the formation of MAC (CD59). Soluble regulators such as C4BP, CFH and FHL1 recognize self surface pattern-like glycosaminoglycans and further impair activation. Complement components interact with other biological systems. Upon microbial infection complement acts in cooperation with Toll-like receptors (TLRs) to amplify innate host defense. Anaphylatoxin C5a binds C5a receptor (C5aR) resulting in a synergistic enhancement of the TLR and C5aR-mediated proinflammatory cytokine response to infection. This interplay is negatively modulated by co-ligation of TLR and the second C5a receptor, C5L2, suggesting the existence of complex immunomodulatory interactions (Kohl J 2006; Hajishengallis G and Lambris JD 2010). In addition to C5aR and C5L2, complement receptor 3 (CR3) facilitates TLR2 or TLR4 signaling pathways by promoting a recruitment of their sorting adaptor TIRAP (MAL) to the receptor complex (van Bruggen R et al. 2007; Kagan JC and Medzhitov R 2006). Complement may activate platelets or facilitate biochemical and morphological changes in the endothelium potentiating coagulation and contributing to homeostasis in response to injury (Oikonomopoulou K et al. 2012). The interplay of complement and coagulation also involves cleavage of C3 and C5 convertases by coagulation proteases, generating biologically active anaphylatoxins (Amara U et al. 2010). Complement is believed to link the innate response to both humoral and cell-mediated immunity (Toapanta FR and Ross TM 2006; Mongini PK et al. 1997). The majority of published data is based on experiments using mouse as a model organism. Further characterization of the influence of complement on B or T cell activation is required for the human system, since differences between murine models and the human system are not yet fully determined. Complement is also involved in regulation of mobilization and homing of hematopoietic stem/progenitor cells (HSPCs) from bone marrow to the circulation and peripheral tissue in order to accommodate blood cell replenishment (Reca R et al. 2006). Thus, the complement system orchestrates the host defense by sensing a danger signal and transmitting it into specific cellular responses while extensively communicating with associated biological pathways ranging from immunity and inflammation to homeostasis and development. Originally the larger fragment of Complement Factor 2 (C2) was designated 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. Recent literature may use the updated nomenclature and refer to the larger C2 fragment as C2b, and refer to the classical C3 convertase as C4bC2b. Throughout this pathway Reactome adheres to the original convention to agree with the current (Sep 2013) Uniprot names for C2 fragments. The complement cascade pathway is organised into the following sections: initial triggering, activation of C3 and C5, terminal pathway and regulation.

Icon (3 results from a total of 3)

C4b

Species: Homo sapiens
C4b is derived from native C4 upon cleavage and release of C4a. It is prepared by cleavage of purified C4 with the classical pathway activated protease C1s enzyme

C2

Species: Homo sapiens
Component C2 which is part of the classical pathway of the complement system is cleaved by activated factor C1 into two fragments: C2b and C2a. C2a, a serine protease, then combines with complement factor C4b to generate the C3 or C5 convertase

C4

Species: Homo sapiens
Non-enzymatic component of C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. Covalently binds to immunoglobulins and immune complexes and enhances the solubilization of immune aggregates and the clearance of IC through CR1 on erythrocytes. C4A isotype is responsible for effective binding to form amide bonds with immune aggregates or protein antigens, while C4B isotype catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens
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