Complement membrane attack complex: Difference between revisions
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The '''membrane attack complex''' ('''MAC''') is typically formed on the surface of [[pathogen]]ic [[bacteria]]l [[Cell (biology)|cell]]s as a result of the activation of the host's [[Alternative complement pathway|alternative pathway]] and the [[Classical complement pathway|classical 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.<ref name="PUB00001056">{{cite journal |doi=10.1016/0955-0674(91)90045-Z |author=Peitsch MC, Tschopp J |title=Assembly of macromolecular pores by immune defense systems |journal=Curr. Opin. Cell Biol. |volume=3 |issue=4 |pages=710–716 |year=1991 |pmid=1722985}}</ref><ref name="PUB00006592">{{cite journal |author=Reid KBM |title= |journal= |volume= |issue= |pages=189–241 |year=1988}}</ref> |
The '''membrane attack complex''' ('''MAC''') is typically formed on the surface of [[pathogen]]ic [[bacteria]]l [[Cell (biology)|cell]]s as a result of the activation of the host's [[Alternative complement pathway|alternative pathway]] and the [[Classical complement pathway|classical 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.<ref name="PUB00001056">{{cite journal |doi=10.1016/0955-0674(91)90045-Z |author=Peitsch MC, Tschopp J |title=Assembly of macromolecular pores by immune defense systems |journal=Curr. Opin. Cell Biol. |volume=3 |issue=4 |pages=710–716 |year=1991 |pmid=1722985}}</ref><ref name="PUB00006592">{{cite journal |author=Reid KBM |title= |journal= |volume= |issue= |pages=189–241 |year=1988}}</ref> |
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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<ref name="PUB00000295">{{cite journal |doi=10.1021/bi00417a050 |author=Stanley KK, Marazziti D, Eggertsen G, Fey GH |title=Relationships between the gene and protein structure in human complement component C9 |journal=Biochemistry |volume=27 |issue=17 |pages=6529–6534 |year=1988 |pmid=3219351}}</ref><ref name="PUB00001141">{{cite journal |author=Stanley KK, Luzio JP, Tschopp J, Kocher HP, Jackson P |title=The sequence and topology of human complement component C9 |journal=EMBO J. |volume=4 |issue=2 |pages=375–382 |year=1985 |pmid=4018030 |pmc=554196}}</ref><ref name="PUB00004608">{{cite journal |doi=10.1073/pnas.81.23.7298 |author=Fey GH, Hugli TE, Podack ER, Gehring MR, Kan CC, DiScipio RG |title=Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=81 |issue=23 |pages=7298–7302 |year=1984 |pmid=6095282 |pmc=392133}}</ref> and acts as a catalyst in the polymerization of C9. |
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<ref name="PUB00000295">{{cite journal |doi=10.1021/bi00417a050 |author=Stanley KK, Marazziti D, Eggertsen G, Fey GH |title=Relationships between the gene and protein structure in human complement component C9 |journal=Biochemistry |volume=27 |issue=17 |pages=6529–6534 |year=1988 |pmid=3219351}}</ref><ref name="PUB00001141">{{cite journal |author=Stanley KK, Luzio JP, Tschopp J, Kocher HP, Jackson P |title=The sequence and topology of human complement component C9 |journal=EMBO J. |volume=4 |issue=2 |pages=375–382 |year=1985 |pmid=4018030 |pmc=554196}}</ref><ref name="PUB00004608">{{cite journal |doi=10.1073/pnas.81.23.7298 |author=Fey GH, Hugli TE, Podack ER, Gehring MR, Kan CC, DiScipio RG |title=Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=81 |issue=23 |pages=7298–7302 |year=1984 |pmid=6095282 |pmc=392133}}</ref> and acts as a catalyst in the polymerization of C9. |
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Active MAC has a subunit composition of C5b-C6-C7-C8-C9{n}. |
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==Structure and function== |
==Structure and function== |
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Revision as of 18:39, 4 November 2014
The membrane attack complex (MAC) is typically formed on the surface of pathogenic bacterial cells as a result of the activation of the host's alternative pathway and the classical 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}.
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 hook up 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
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. This exists on body cells to protect them from MAC. A rare condition, paroxysmal nocturnal haemoglobinuria, results in red cells that lack CD59. These red cells can, therefore, be lysed by MAC.
References
- ^ 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.
- ^ Reid KBM (1988). : 189–241.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ 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.
{{cite journal}}: CS1 maint: multiple names: authors list (link)
External links
- Complement+Membrane+Attack+Complex at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- http://www.lib.mcg.edu/edu/esimmuno/ch2/lysis.htm