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

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

s as a result of the activation of the host's complement system, and as such is an effector of the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

Antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the ...

-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 Lysis ( ) is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ''lysate''. In molecular bi ...

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

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

, 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 ...

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 Protein S (also known as PROS) is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In ...

(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 groups that are part of other molecules, so cause agglutination of particular cells or precipitation of glycoconjugates and polysaccharides. Lectins have a role in r ...

and

alternative Alternative or alternate may refer to: Arts, entertainment and media * Alternative (''Kamen Rider''), a character in the Japanese TV series ''Kamen Rider Ryuki'' * ''The Alternative'' (film), a 1978 Australian television film * ''The 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 physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, t ...

''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 are flat sheets that form a continuous barrier around all cells. The cell membranes of almost all organisms and many v ...

. * MAC has a

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are no ...

''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 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood characterized by destruction of red blood cells by the complement system, a part of the body's innate immune system. This destructive process occ ...

, results in red blood cells that lack CD59. These cells can, therefore, be lysed by MAC.

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 surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mec ...

and little to no

glycocalyx The glycocalyx, also known as the pericellular matrix, is a glycoprotein and glycolipid covering that surrounds the cell membranes of bacteria, epithelial cells, and other cells. In 1970, Martinez-Palomo discovered the cell coating in animal cell ...

References

External links

* * {{Complement system Complement system Immune system Immunology