MACPF explained

See also: Complement membrane attack complex.

The Membrane Attack Complex/Perforin (MACPF) superfamily, sometimes referred to as the MACPF/CDC superfamily,[1] is named after a domain that is common to the membrane attack complex (MAC) proteins of the complement system (C6, C7, C8α, C8β and C9) and perforin (PF). Members of this protein family are pore-forming toxins (PFTs).[2] In eukaryotes, MACPF proteins play a role in immunity and development.[3]

Archetypal members of the family are complement C9 and perforin, both of which function in human immunity.[4] C9 functions by punching holes in the membranes of Gram-negative bacteria. Perforin is released by cytotoxic T cells and lyses virally infected and transformed cells. In addition, perforin permits delivery of cytotoxic proteases called granzymes that cause cell death.[5] Deficiency of either protein can result in human disease.[6] [7] Structural studies reveal that MACPF domains are related to cholesterol-dependent cytolysins (CDCs), a family of pore forming toxins previously thought to only exist in bacteria.[8] [9]

Families

As of early 2016, there are three families belonging to the MACPF superfamily:

Membrane Attack Complex/Perforin (MACPF) Family

Proteins containing MACPF domains play key roles in vertebrate immunity, embryonic development, and neural-cell migration.[10] The ninth component of complement and perforin form oligomeric pores that lyse bacteria and kill virus-infected cells, respectively. The crystal structure of a bacterial MACPF protein, Plu-MACPF from Photorhabdus luminescens was determined .[11] The MACPF domain is structurally similar to pore-forming cholesterol-dependent cytolysins from gram-positive bacteria, suggesting that MACPF proteins create pores and disrupt cell membranes similar to cytolysin. A representative list of proteins belonging to the MACPF family can be found in the Transporter Classification Database.

Biological roles of MACPF domain containing proteins

Many proteins belonging to the MACPF superfamily play key roles in plant and animal immunity.

Complement proteins C6-C9 all contain a MACPF domain and assemble into the membrane attack complex. C6, C7 and C8β appear to be non-lytic and function as scaffold proteins within the MAC. In contrast both C8α and C9 are capable of lysing cells. The final stage of MAC formation involves polymerisation of C9 into a large pore that punches a hole in the outer membrane of gram-negative bacteria.

Perforin is stored in granules within cytotoxic T-cells and is responsible for killing virally infected and transformed cells. Perforin functions via two distinct mechanisms. Firstly, like C9, high concentrations of perforin can form pores that lyse cells. Secondly, perforin permits delivery of the cytotoxic granzymes A and B into target cells. Once delivered, granzymes are able to induce apoptosis and cause target cell death.[5] [12]

The plant protein CAD1 (TC# 1.C.39.11.3) functions in the plant immune response to bacterial infection.[13] [14]

The sea anemone Actineria villosa uses a MACPF (AvTX-60A; TC# 1.C.39.10.1)protein as a lethal toxin.[15]

MACPF proteins are also important for the invasion of the Malarial parasite into the mosquito host and the liver.[16] [17]

Not all MACPF proteins function in defence or attack. For example, astrotactin-1 (TC# 9.B.87.3.1) is involved in neural cell migration in mammals and apextrin (TC# 1.C.39.7.4) is involved in sea urchin (Heliocidaris erythrogramma) development.[18] [19] Drosophila Torso-like protein (TC# 1.C.39.15.1), which controls embryonic patterning,[20] also contains a MACPF domain. Its function is implicated in a receptor tyrosine kinase signaling pathway that specifies differentiation and terminal cell fate.

Functionally uncharacterised MACPF proteins are sporadically distributed in bacteria. Several species of Chlamydia contain MACPF proteins.[21] The insect pathogenic bacteria Photorhabdus luminescens also contains a MACPF protein, however, this molecule appears non-lytic.[8]

Structure and mechanism

The X-ray crystal structure of Plu-MACPF, a protein from the insect pathogenic enterobacteria Photorhabdus luminescens has been determined (figure 1).http://www.rcsb.org/pdb/explore/explore.do?structureId=2QP2 These data reveal that the MACPF domain is homologous to pore forming cholesterol dependent cytolysins (CDC's) from gram-positive pathogenic bacteria such as Clostridium perfringens (which causes gas gangrene). The amino acid sequence identity between the two families is extremely low, and the relationship is not detectable using conventional sequence based data mining techniques.[8]

It is suggested that MACPF proteins and CDCs form pores in the same way (figure 1).[8] Specifically it is hypothesised that MACPF proteins oligomerise to form a large circular pore (figure 2). A concerted conformational change within each monomer then results in two α-helical regions unwinding to form four amphipathic β-strands that span the membrane of the target cell.[8] Like CDC's MACPF proteins are thus β-pore forming toxins that act like a molecular hole punch.

Other crystal structures for members of the MACPF superfamily can be found in RCSB: i.e.,,,,,

Control of MACPF proteins

Complement regulatory proteins such as CD59 function as MAC inhibitors and prevent inappropriate activity of complement against self cells (Figure 3). Biochemical studies have revealed the peptide sequences in C8α and C9 that bind to CD59.[22] [23] Analysis of the MACPF domain structures reveals that these sequences map to the second cluster of helices that unfurl to span the membrane. It is therefore suggested that CD59 directly inhibits the MAC by interfering with conformational change in one of the membrane spanning regions.[8]

Other proteins that bind to the MAC include C8γ. This protein belongs to the lipocalin family and interacts with C8α. The binding site on C8α is known, however, the precise role of C8γ in the MAC remains to be understood.[24] [25]

Role in human disease

Deficiency of C9, or other components of the MAC results in an increased susceptibility to diseases caused by gram-negative bacteria such as meningococcal meningitis.[26] Overactivity of MACPF proteins can also cause disease. Most notably, deficiency of the MAC inhibitor CD59 results in an overactivity of complement and Paroxysmal nocturnal hemoglobinuria.[27]

Perforin deficiency results in the commonly fatal disorder familial hemophagocytic lymphohistiocytosis (FHL or HLH).[6] This disease is characterised by an overactivation of lymphocytes which results in cytokine mediated organ damage.[28]

The MACPF protein DBCCR1 may function as a tumor suppressor in bladder cancer.[29]

Human proteins containing this domain

C6

C7; C8A; C8B; C9; FAM5B; FAM5C; MPEG1;PRF1

Notes and References

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  2. Peitsch MC, Tschopp J . Assembly of macromolecular pores by immune defense systems . Curr. Opin. Cell Biol. . 3 . 4 . 710–6 . 1991 . 1722985 . 10.1016/0955-0674(91)90045-Z.
  3. The MACPF/CDC family of pore-forming toxins. Cellular Microbiology. 2008-09-01. 1462-5822. 2654483. 18564372. 1765–1774. 10. 9. 10.1111/j.1462-5822.2008.01191.x. en. Carlos J.. Rosado. Stephanie. Kondos. Tara E.. Bull. Michael J.. Kuiper. Ruby H. P.. Law. Ashley M.. Buckle. Ilia. Voskoboinik. Phillip I.. Bird. Joseph A.. Trapani.
  4. Tschopp J, Masson D, Stanley KK . Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis . Nature . 322 . 6082 . 831–4 . 1986 . 2427956 . 10.1038/322831a0. 1986Natur.322..831T . 4330219 .
  5. Voskoboinik I, Smyth MJ, Trapani JA . Perforin-mediated target-cell death and immune homeostasis . Nat. Rev. Immunol. . 6 . 12 . 940–52 . 2006 . 17124515 . 10.1038/nri1983. 39504110 .
  6. Voskoboinik I, Sutton VR, Ciccone A, etal . Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function . Blood . 110 . 4 . 1184–90 . 2007 . 17475905 . 10.1182/blood-2007-02-072850. free .
  7. Witzel-Schlömp K, Späth PJ, Hobart MJ, etal . The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure . J. Immunol. . 158 . 10 . 5043–9 . 1997 . 10.4049/jimmunol.158.10.5043 . 9144525 . 22684521 .
  8. Rosado CJ, Buckle AM, Law RH, etal . A Common Fold Mediates Vertebrate Defense and Bacterial Attack . Science. 317. 5844. 1548–51. 2007 . 17717151 . 10.1126/science.1144706. 2007Sci...317.1548R . 20372720 . free .
  9. Structure of C8-MACPF Reveals Mechanism of Membrane Attack in Complement Immune Defense . Michael A. Hadders . Dennis X. Beringer . Piet Gros . amp . Science . 10.1126/science.1147103 . 1552–1554 . 2007 . 317 . 17872444 . 5844. 1874/26831 . 44959101 . free .
  10. Disparate proteins use similar architectures to damage membranes. Trends in Biochemical Sciences. 2008-10-01. 0968-0004. 18778941. 482–490. 33. 10. 10.1016/j.tibs.2008.07.004. Gregor. Anderluh. Jeremy H.. Lakey.
  11. A common fold mediates vertebrate defense and bacterial attack. Science . 2007-09-14. 1095-9203. 17717151. 1548–1551. 317. 5844. 10.1126/science.1144706. 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. 2007Sci...317.1548R . 20372720 . free.
  12. Kaiserman D, Bird CH, Sun J, etal . The major human and mouse granzymes are structurally and functionally divergent . J. Cell Biol. . 175 . 4 . 619–30 . 2006 . 17116752 . 10.1083/jcb.200606073 . 2064598.
  13. Morita-Yamamuro C, Tsutsui T, Sato M, etal . The Arabidopsis gene CAD1 controls programmed cell death in the plant immune system and encodes a protein containing a MACPF domain . Plant Cell Physiol. . 46 . 6 . 902–12 . 2005 . 15799997 . 10.1093/pcp/pci095. free .
  14. Salicylic acid and a chitin elicitor both control expression of the CAD1 gene involved in the plant immunity of Arabidopsis. Bioscience, Biotechnology, and Biochemistry. 2006-09-01. 0916-8451. 16960394. 2042–2048. 70. 9. 10.1271/bbb.50700. Tomokazu. Tsutsui. Chizuko. Morita-Yamamuro. Yutaka. Asada. Eiichi. Minami. Naoto. Shibuya. Akira. Ikeda. Junji. Yamaguchi. 2115/14840. 37799485. free.
  15. Oshiro N, Kobayashi C, Iwanaga S, etal . A new membrane-attack complex/perforin (MACPF) domain lethal toxin from the nematocyst venom of the Okinawan sea anemone Actineria villosa . Toxicon . 43 . 2 . 225–8 . 2004 . 15019483 . 10.1016/j.toxicon.2003.11.017.
  16. Kadota K, Ishino T, Matsuyama T, Chinzei Y, Yuda M . Essential role of membrane-attack protein in malarial transmission to mosquito host . Proc. Natl. Acad. Sci. U.S.A. . 101 . 46 . 16310–5 . 2004 . 15520375 . 10.1073/pnas.0406187101 . 524694. free .
  17. Ishino T, Chinzei Y, Yuda M . A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection . Cell. Microbiol. . 7 . 2 . 199–208 . 2005 . 15659064 . 10.1111/j.1462-5822.2004.00447.x. 19341572 .
  18. Zheng C, Heintz N, Hatten ME . CNS gene encoding astrotactin, which supports neuronal migration along glial fibers . Science . 272 . 5260 . 417–9 . 1996 . 8602532 . 10.1126/science.272.5260.417. 1996Sci...272..417Z . 206576029 .
  19. Haag ES, Sly BJ, Andrews ME, Raff RA . Apextrin, a novel extracellular protein associated with larval ectoderm evolution in Heliocidaris erythrogramma . Dev. Biol. . 211 . 1 . 77–87 . 1999 . 10373306 . 10.1006/dbio.1999.9283. free .
  20. Martin JR, Raibaud A, Ollo R . Terminal pattern elements in Drosophila embryo induced by the torso-like protein . Nature . 367 . 6465 . 741–5 . 1994 . 8107870 . 10.1038/367741a0. 1994Natur.367..741M . 4274979 .
  21. Ponting CP . Chlamydial homologues of the MACPF (MAC/perforin) domain . Curr. Biol. . 9 . 24 . R911–3 . 1999 . 10608922 . 10.1016/S0960-9822(00)80102-5. 7748405 . free .
  22. Huang Y, Qiao F, Abagyan R, Hazard S, Tomlinson S . Defining the CD59-C9 binding interaction . J. Biol. Chem. . 281 . 37 . 27398–404 . 2006 . 16844690 . 10.1074/jbc.M603690200 . free .
  23. Lockert DH, Kaufman KM, Chang CP, Hüsler T, Sodetz JM, Sims PJ . Identity of the segment of human complement C8 recognized by complement regulatory protein CD59 . J. Biol. Chem. . 270 . 34 . 19723–8 . 1995 . 7544344 . 10.1074/jbc.270.8.3483. free .
  24. Schreck SF, Plumb ME, Platteborze PL, etal . Expression and characterization of recombinant subunits of human complement component C8: further analysis of the function of C8 alpha and C8 gamma . J. Immunol. . 161 . 1 . 311–8 . 1998 . 10.4049/jimmunol.161.1.311 . 9647238 . 86614986 . free .
  25. Lovelace LL, Chiswell B, Slade DJ, Sodetz JM, Lebioda L . Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: Implications for C8gamma ligand binding . Molecular Immunology. 45. 3. 750–6. 2007 . 17692377 . 10.1016/j.molimm.2007.06.359.
  26. Kira R, Ihara K, Takada H, Gondo K, Hara T . Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency . Hum. Genet. . 102 . 6 . 605–10 . 1998 . 9703418 . 10.1007/s004390050749. 3227108 .
  27. Walport . Mark J. . Mark Walport. Complement. First of two parts . N. Engl. J. Med. . 344 . 14 . 1058–66 . 2001 . 11287977 . 10.1056/NEJM200104053441406.
  28. Verbsky JW, Grossman WJ . Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives . Ann. Med. . 38 . 1 . 20–31 . 2006 . 16448985 . 10.1080/07853890500465189. 30781596 .
  29. Wright KO, Messing EM, Reeder JE . DBCCR1 mediates death in cultured bladder tumor cells . Oncogene . 23 . 1 . 82–90 . 2004 . 14712213 . 10.1038/sj.onc.1206642. 3620390 .

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