Complement membrane attack complex

Complement membrane attack complex
A membrane attack complex attached to a pathogenic cell.

The membrane attack complex (MAC) is typically formed on the surface of intruding pathogenic bacterial cells as a result of the activation of the alternative pathway of the complement system, and it is one of the effector proteins of the immune system. The membrane-attack complex (MAC) forms transmembrane channels. These channels disrupt the phospholipid bilayer of target cells, leading to cell lysis and death[1][2].

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-7 complex. The C5b-7 complex binds to C8, which is composed of three chains (alpha, beta, and gamma), thus forming the C5b-8 complex. C5b-8 subsequently binds to C9[3][4][5] and acts as a catalyst in the polymerization of C9. Active MAC has a subunit composition of C5b-C6-C7-C8-C9{n}.

Contents

Structure and function

It is composed of a complex of four complement proteins (C5b, C6, C7, and C8) that bind to the outer surface of the plasma membrane, and many copies of a fifth protein (C9) that hookup to one another, forming a ring in the membrane. C6-C9 all contain a common MACPF domain. [6] This region is homologous to cholesterol-dependent cytolysins from Gram-positive bacteria.[7]

The ring structure formed by C9 is a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive.

Initiation: C5-C7

Membrane attack complex.

The membrane attack complex is initiated when the complement protein C5 convertase cleaves C5 into C5a and C5b.

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.

  • It has a hydrophobic external face allowing it to associate with the lipid bilayer.
  • It has a hydrophilic internal face to allow the passage of water.

Inhibition

CD59 acts to inhibit the complex.

References

  1. ^ Peitsch MC, Tschopp J (1991). "Assembly of macromolecular pores by immune defense systems". Curr. Opin. Cell Biol. 3 (4): 710–716. doi:10.1016/0955-0674(91)90045-Z. PMID 1722985. 
  2. ^ Reid KBM (1988). pp. 189–241. 
  3. ^ Stanley KK, Marazziti D, Eggertsen G, Fey GH (1988). "Relationships between the gene and protein structure in human complement component C9". Biochemistry 27 (17): 6529–6534. doi:10.1021/bi00417a050. PMID 3219351. 
  4. ^ Stanley KK, Luzio JP, Tschopp J, Kocher HP, Jackson P (1985). "The sequence and topology of human complement component C9". EMBO J. 4 (2): 375–382. PMC 554196. PMID 4018030. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=554196. 
  5. ^ Fey GH, Hugli TE, Podack ER, Gehring MR, Kan CC, DiScipio RG (1984). "Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9". Proc. Natl. Acad. Sci. U.S.A. 81 (23): 7298–7302. doi:10.1073/pnas.81.23.7298. PMC 392133. PMID 6095282. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=392133. 
  6. ^ Tschopp J, Masson D, Stanley KK (1986). "Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis". Nature 322 (6082): 831–4. doi:10.1038/322831a0. PMID 2427956. 
  7. ^ Carlos J. Rosado, Ashley M. Buckle, Ruby H. P. Law, Rebecca E. Butcher, Wan-Ting Kan, Catherina H. Bird, Kheng Ung, Kylie A. Browne, Katherine Baran, Tanya A. Bashtannyk-Puhalovich, Noel G. Faux, Wilson Wong, Corrine J. Porter, Robert N. Pike, Andrew M. Ellisdon, Mary C. Pearce, Stephen P. Bottomley, Jonas Emsley, A. Ian Smith, Jamie Rossjohn, Elizabeth L. Hartland, Ilia Voskoboinik, Joseph A. Trapani, Phillip I. Bird, Michelle A. Dunstone, and James C. Whisstock (2007). "A Common Fold Mediates Vertebrate Defense and Bacterial Attack". Science 317 (5844): 1548–51. doi:10.1126/science.1144706. PMID 17717151. 

External links

v · d · eProteins: complement system (C, L, A)
Activators/enzymes
Early
Middle
Late
MAC (C6, C7, C8, C9)
Inhibitors
Complement receptors

M: LMC

cell/phys/auag/auab/comp, igrc

imdf/ipig/hyps/tumr

proc, drug(L3/4)

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