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The Lectin Pathway - I
Sqadia video is the demonstration of The lectin pathway originates with host proteins binding microbial surfaces. Lectins are proteins that recognize and bind to specific carbohydrate targets. Some authors designate MBL pathway - Mannose-Binding Lectin Pathway. The lectin pathway, like the alternative pathway, does not depend on antibody for its activation. However, the mechanism is more like that of the classical pathway. The lectin pathway is activated by binding of MBL to mannose residues on glycoproteins or carbohydrates On the surface of microorganisms including certain strains of Salmonella, Listeria, Neisseria. MBL is an acute phase protein produced in inflammatory responses. Its function in the complement pathway is similar to that of C1q, which it resembles in structure. After MBL binds to the surface of a cell or pathogen. MBL-associated serine proteases, MASP-1 and MASP-2 bind to MBL. The active complex formed by this association causes cleavage and activation of C4 and C2. This means of activating the C2–C4 components to form a C5 convertase without need for specific antibody binding represents an important innate defense mechanism.
The Lectin Pathway - II
The terminal sequence of complement activation involves C5b, C6, C7, C8, and C9, which interact sequentially to form a macromolecular structure called the membrane-attack complex (MAC). The end result of activating the classical, alternative, or lectin pathways is production of an active C5 convertase. This enzyme cleaves C5, which contains two protein chains, α and β. After binding of C5 to the non-enzymatic c3b component of the convertase the amino terminus of the α chain is cleaved. This generates the small c5a fragment which diffuses away. The large c5b fragment provides a binding site for the subsequent components of MAC. Up to this point, all the complement reactions take place on the hydrophilic surface of membranes or on immune complexes in the fluid phase. If the reaction occurs on a target-cell membrane, the hydrophobic binding sites enable the C5b67 complex to insert into the phospholipid bilayer. If, however, the reaction occurs on an immune complex or other non-cellular activating surface. Hydrophobic binding sites cannot anchor the complex and it is released. Binding of C8 to membrane-bound c5b67 Induces a conformational change in C8 so that it too undergoes a hydrophilic-amphiphilic structural transition. The final step in formation of the MAC is the binding and polymerization of C9 A perforin-like molecule, to the c5b678 complex. The completed MAC, which has a tubular form and functional pore size of 70–100 Å, consists of a C5b678 complex surrounded by a poly-C9 complex.
Regulation of the Complement System - I
Many elements of the complement system are capable of attacking host cells as well as foreign cells and microorganisms. Elaborate regulatory mechanisms have evolved to restrict complement activity to designated targets. A general mechanism of regulation in all complement pathways is the inclusion of highly labile components that undergo spontaneous inactivation. A series of regulatory proteins can inactivate various complement components. Regulation before assembly of convertase activity involves C1 inhibitor (C1Iab) that binds C1r2s2, causing dissociation from C1q. The reaction catalyzed by the C3 convertase enzymes of the classical, lectin, and alternative pathways is the major amplification step in complement activation, generating hundreds of molecules of C3b. The C3b generated by these enzymes has the potential to bind to nearby cells, mediating damage to the healthy cells. The potential destruction of healthy host cells by C3b is further limited by a family of related proteins that regulate C3 convertase activity in the classical and alternative pathways. All these proteins are encoded at a single location on chromosome 1 in humans known as the regulators of complement activation (RCA) gene cluster. In the classical and lectin pathways, three structurally distinct RCA proteins act similarly to prevent assembly of C3 convertase. These regulatory proteins include soluble C4b-binding protein (C4bBP) and two membrane-bound proteins, complement receptor type 1 (CR1) and membrane cofactor protein (MCP). Association of C4b and C2a is blocked by binding C4b-binding protein (C4bBP), complement receptor type I, or membrane cofactor protein (MCP). Inhibitor-bound C4b is cleaved by Factor 1.
Regulation of the Complement System - II
A similar regulatory sequence operates to prevent assembly of the C3 convertase C3̅b̅B̅̅b̅ in the alternative pathway. In this case CR1, MCP, or a regulatory component called factor H binds to C3b and prevents its association with factor B. Further cleavage of iC3b by factor I releases C3c and leaves C3dg bound to the membrane. In alternative pathway, CR1, MCP, or Factor H prevent binding of C3b and Factor B. Several RCA proteins also act on the assembled C3 convertase causing it to dissociate. In addition, decay accelerating factor (DAF or CD55), which is a glycoprotein anchored covalently to a glycophospholipid membrane protein, has the ability to dissociate C3 convertase. Once dissociation of the C3 convertase occurs Factor I cleaves the remaining membrane-bound C4b or C3b component irreversibly inactivating the convertase. Regulatory proteins also operate at the level of the MAC. A serum protein called S protein can bind to C5b67 inducing a hydrophilic transition and reventing insertion of C5b67 into the membrane of nearby cells.
Regulation of the Complement System - III
Complement-mediated lysis is more effective if the complement is from a species different. This phenomenon depends on two membrane proteins that block MAC formation i.e. Homologous restriction factor (HRF) and Membrane inhibitor of reactive lysis (MIRL or CD59). Both HRF and MIRL protect cells from nonspecific complement-mediated lysis by binding to C8, preventing assembly of poly-C9 and blocking formation of MAC. In the classical pathway, C4bBP, CR1, or MCP bind to C4b and act as cofactors for factor I–mediated cleavage of C4b. In the alternative pathway, factor H, CR1, or MCP bind to CCB and act as cofactors for factor I–mediated cleavage of C4b.