The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of

pathogen In biology, a pathogen (, "suffering", "passion" and , "producer of"), in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a Germ theory of d ...

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

s as a result of the activation of the host's

complement system The complement system, also known as complement cascade, is a part of the humoral, innate immune system and enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inf ...

, and as such is an effector of the

immune system The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to bacteria, as well as Tumor immunology, cancer cells, Parasitic worm, parasitic ...

Antibody An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as pathogenic bacteria, bacteria and viruses, includin ...

-mediated complement activation leads to MAC deposition on the surface of infected cells. Assembly of the MAC leads to pores that disrupt the

of target cells, leading to cell lysis and death. The MAC is composed of the complement components C5b, C6, C7, C8 and several C9 molecules. A number of proteins participate in the assembly of the MAC. Freshly activated C5b binds to C6 to form a C5b-6 complex, then to C7 forming the C5b-6-7 complex. The C5b-6-7 complex binds to C8, which is composed of three chains (alpha, beta, and gamma), thus forming the C5b-6-7-8 complex. C5b-6-7-8 subsequently binds to C9 and acts as a catalyst in the polymerization of C9.

Structure and function

MAC is composed of a complex of four complement

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s (C5b, C6, C7, and C8) that bind to the outer surface of the

plasma membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

, and many copies of a fifth protein (C9) that hook up to one another, forming a ring in the membrane. C6-C9 all contain a common MACPF domain. This region is homologous to cholesterol-dependent cytolysins from Gram-positive bacteria. The ring structure formed by C9 is a pore in the membrane that allows free

diffusion Diffusion is the net movement of anything (for example, atoms, ions, molecules, energy) generally from a region of higher concentration to a region of lower concentration. Diffusion is driven by a gradient in Gibbs free energy or chemical p ...

of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive. If the pre-MAC complexes of C5b-7, C5b-8 or C5b-9 do not insert into a membrane, they can form inactive complexes with Protein S (sC5b-7, sC5b-8 and sC5b-9). These fluid phase complexes do not bind to cell membranes and are ultimately scavenged by clusterin and vitronectin, two regulators of complement.

Initiation: C5-C7

The membrane attack complex is initiated when the complement protein C5 convertase cleaves C5 into C5a and C5b. All three pathways of the complement system ( classical,

lectin Lectins are carbohydrate-binding proteins that are highly specific for sugar Moiety (chemistry), groups that are part of other molecules, so cause agglutination (biology), agglutination of particular cells or precipitation of glycoconjugates an ...

and alternative pathways) initiate the formation of MAC. Another complement protein, C6, binds to C5b. The C5bC6 complex is bound by C7. This junction alters the configuration of the protein molecules exposing a hydrophobic site on C7 that allows the C7 to insert into the phospholipid bilayer of the pathogen.

Polymerization: C8-C9

Similar hydrophobic sites on C8 and C9 molecules are exposed when they bind to the complex, so they can also insert into the bilayer. C8 is a complex made of the two proteins C8-beta and C8 alpha-gamma. C8 alpha-gamma has the hydrophobic area that inserts into the bilayer. C8 alpha-gamma induces the polymerization of 10-16 molecules of C9 into a pore-forming structure known as the membrane attack complex. * MAC has a

hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...

''external face'' allowing it to associate with the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

. * MAC has a hydrophilic ''internal face'' to allow the passage of water. Multiple molecules of C9 can join spontaneously in concentrated solution to form polymers of C9. These polymers can also form a tube-like structure.

Inhibition

CD59 acts to inhibit the complex. This exists on body cells to protect them from MAC. A rare condition, paroxysmal nocturnal haemoglobinuria, results in red blood cells that lack CD59. These cells can, therefore, be lysed by MAC. Inhibition of MAC has been shown to reduce inflammation and neuroaxonal loss at 72 hours post-Traumatic Brain Injury (TBI) event, potentially preventing neurological damage, especially in cases with acquired sepsis or respiratory failure.

Pathology

Deficiencies of C5 to C9 components do not lead to a generalized susceptibility to infections but only to an increased susceptibility to '' Neisseria'' infections, since ''Neisseria'' have a thin

cell wall A cell wall is a structural layer that surrounds some Cell type, cell types, found immediately outside the cell membrane. It can be tough, flexible, and sometimes rigid. Primarily, it provides the cell with structural support, shape, protection, ...

and little to no glycocalyx.

References

External links

* * {{Complement system Complement system Immune system Immunology