The membrane attack complex (MAC) or terminal complement complex (TCC) is a complex of proteins typically formed on the surface of pathogencell membranes as a result of the activation of the host's complement system, and as such is an effector of the immune system. Antibody-mediated complement activation leads to MAC deposition on the surface of infected cells.[1] Assembly of the MAC leads to pores that disrupt the cell membrane of target cells, leading to cell lysis and death.[2]
A membrane attack complex attached to a pathogenic cell
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[3][4][5] and acts as a catalyst in the polymerization of C9.
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, 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.
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.[8]
Initiation: C5-C7
Membrane attack complex
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 and alternative pathways) initiate the formation of MAC.
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.[2]
MAC has a hydrophilicinternal 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.
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,[9] since Neisseria have a thin cell wall and little to no glycocalyx.[10]
^Xie CB, Jane-Wit D, Pober JS (2020). "Complement Membrane Attack Complex: New Roles, Mechanisms of Action, and Therapeutic Targets". The American Journal of Pathology. 190 (6): 1138–1150. doi:10.1016/j.ajpath.2020.02.006. PMC7280757. PMID 32194049.
^ abJaneway, CA Jr; Travers P; Walport M; et al. (2001). "The complement system and innate immunity". Immunobiology: The Immune System in Health and Disease. New York: Garland Science. Retrieved 4 January 2018.
^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.
^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. doi:10.1002/j.1460-2075.1985.tb03639.x. PMC554196. PMID 4018030.
^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. Bibcode:1984PNAS...81.7298D. doi:10.1073/pnas.81.23.7298. PMC392133. PMID 6095282.
^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. Bibcode:1986Natur.322..831T. doi:10.1038/322831a0. PMID 2427956. S2CID 4330219.
^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 & James C. Whisstock (2007). "A Common Fold Mediates Vertebrate Defense and Bacterial Attack". Science. 317 (5844): 1548–51. Bibcode:2007Sci...317.1548R. doi:10.1126/science.1144706. PMID 17717151. S2CID 20372720.
^Hadders, MA (2012). "Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9". Cell Rep. 1 (3): 200–207. doi:10.1016/j.celrep.2012.02.003. PMC3314296. PMID 22832194.
^Ronald Hoffman, Leslie E. Silberstein, Helen Heslop, Jeffrey Weitz, Hematology: Basic Principles and Practice, 6th ed., Elsevier, 2013, page 231.
^Abbas, Abul K. (2020). Basic Immunology: Functions and Disorders of the Immune System (6th ed.). Philadelphia, PA: Elsevier. pp. 158–176. ISBN978-0-323-54943-1.
External links
Media related to Complement membrane attack complex at Wikimedia Commons
Complement+Membrane+Attack+Complex at the US National Library of Medicine Medical Subject Headings (MeSH)
March 04, 2023
complement, membrane, attack, complex, also, macpf, membrane, attack, complex, terminal, complement, complex, complex, proteins, typically, formed, surface, pathogen, cell, membranes, result, activation, host, complement, system, such, effector, immune, system. See also MACPF The membrane attack complex MAC or terminal complement complex TCC is a complex of proteins typically formed on the surface of pathogen cell membranes as a result of the activation of the host s complement system and as such is an effector of the immune system Antibody mediated complement activation leads to MAC deposition on the surface of infected cells 1 Assembly of the MAC leads to pores that disrupt the cell membrane of target cells leading to cell lysis and death 2 Membrane attack complex Terminal complement complex C5b 9 A membrane attack complex attached to a pathogenic cell 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 3 4 5 and acts as a catalyst in the polymerization of C9 Contents 1 Structure and function 2 Initiation C5 C7 3 Polymerization C8 C9 4 Inhibition 5 Pathology 6 See also 7 References 8 External linksStructure and function EditMAC 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 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 8 Initiation C5 C7 Edit Membrane attack complex 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 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 EditSimilar 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 2 MAC has a hydrophobic external face allowing it to associate with the lipid bilayer 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 EditCD59 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 Pathology EditDeficiencies of C5 to C9 components do not lead to a generalized susceptibility to infections but only to an increased susceptibility to Neisseria infections 9 since Neisseria have a thin cell wall and little to no glycocalyx 10 See also EditTerminal complement pathway deficiency Paroxysmal nocturnal haemoglobinuria Perforin Pore forming toxinReferences Edit Xie CB Jane Wit D Pober JS 2020 Complement Membrane Attack Complex New Roles Mechanisms of Action and Therapeutic Targets The American Journal of Pathology 190 6 1138 1150 doi 10 1016 j ajpath 2020 02 006 PMC 7280757 PMID 32194049 a b Janeway CA Jr Travers P Walport M et al 2001 The complement system and innate immunity Immunobiology The Immune System in Health and Disease New York Garland Science Retrieved 4 January 2018 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 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 doi 10 1002 j 1460 2075 1985 tb03639 x PMC 554196 PMID 4018030 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 Bibcode 1984PNAS 81 7298D doi 10 1073 pnas 81 23 7298 PMC 392133 PMID 6095282 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 Bibcode 1986Natur 322 831T doi 10 1038 322831a0 PMID 2427956 S2CID 4330219 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 amp James C Whisstock 2007 A Common Fold Mediates Vertebrate Defense and Bacterial Attack Science 317 5844 1548 51 Bibcode 2007Sci 317 1548R doi 10 1126 science 1144706 PMID 17717151 S2CID 20372720 Hadders MA 2012 Assembly and regulation of the membrane attack complex based on structures of C5b6 and sC5b9 Cell Rep 1 3 200 207 doi 10 1016 j celrep 2012 02 003 PMC 3314296 PMID 22832194 Ronald Hoffman Leslie E Silberstein Helen Heslop Jeffrey Weitz Hematology Basic Principles and Practice 6th ed Elsevier 2013 page 231 Abbas Abul K 2020 Basic Immunology Functions and Disorders of the Immune System 6th ed Philadelphia PA Elsevier pp 158 176 ISBN 978 0 323 54943 1 External links Edit Media related to Complement membrane attack complex at Wikimedia Commons Complement Membrane Attack Complex at the US National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Complement membrane attack complex amp oldid 1118509983, wikipedia, wiki, book, books, library,
