MACPF

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Macpf is a family of proteins whose representatives a macpf - protein domain possess. MACPF proteins are e.g. B. C6, C7, C8α, C8β and C9 of the membrane attack complex (MAC) of the complement system and perforin (PF), where the name comes from. Analogous to the pore-forming toxins, they serve to form a pore in bacteria, fungi, virally infected and degenerated cells as part of the immune response .

properties

MACPF proteins are registered in various databases (Pfam = PF01823, InterPro = IPR001862, SMART = MACPF, PROSITE = PDOC00251, TCDB = 1.C.39). The protein C9 perforates pathogenic gram-negative bacteria and virally infected cells and thus leads to lysis and cell death . Perforin is released by cytotoxic T cells and, in addition to lysis, allows granzyme to flow into the cell to be lysed. A genetic defect in one of the two genes leads to diseases. In terms of their protein structure, MACPF are related to the cholesterol-dependent cytolysins .

To date, around 500 members of the MACPF family have been described. In humans these are C6, C7, C8A, C8B, C9, FAM5B , FAM5C , MPEG1 and PRF1 . The vegetable protein CAD1 also serves to ward off infection. The sea ​​anemone Actineria villosa uses a MACPF protein as a toxin . MACPF proteins are used by Plasmodium spp. to penetrate the cells of the mosquito host and human hepatocytes .

Not all MACPF proteins are used for defense. Astrotactin occurs in the cell migration of neurons . Apextrin is involved in the development of sea ​​urchins . The torso-like protein in Drosophila controls embryonic pattern formation. The involvement of a possible lytic function of these proteins is unknown.

The MACPF proteins in Chlamydia spp. and in Photorhabdus luminescens have not yet been further characterized . The latter is believed to be non-lytic.

Structure and mechanism

In terms of their protein structure, MACPF proteins are related to the cholesterol-dependent cytolysins . The protein structure of Plu-MACPF, the MACPF protein from the insect pathogenic enterobacterium Photorhabdus luminescens , is homologous to the pore-forming toxins from Clostridium perfringens . However, the conservation of the amino acid sequence is low, which is why the usefulness of sequence-based search algorithms is limited.

Presumably, MACPF proteins and cholesterol-dependent cytolysins form pores via the same mechanism. A concerted change in protein folding in each monomer unwinds two α-helices , from which four amphipathic β-strands are formed, which pierce the cell membrane and expand the pore into the biomembrane .

mechanism
Structure of Perfringolysin O. and Plu-MACPF. The α-helices are colored pink.
Model based on pneumolysin.
Binding proteins
NMR structure of the CD59 . 1ERG .
Crystal structure of C8γ (green) with a peptide of C8α (cyan).

Diseases

Genetic defects in C9 or other parts of the MAC increases the risk of meningococcal - meningitis . Excessive activation of the MACPF proteins due to a lack of the inhibitor CD59s leads to paroxysmal nocturnal hemoglobinuria .

A perforation deficiency leads to hemophagocytic lymphohistiocytosis (FHL or HLH).

The MACPF protein DBCCR1 is believed to be a tumor suppressor in bladder cancer .

Web links

Individual evidence

  1. ^ Peitsch MC, Tschopp J: Assembly of macromolecular pores by immune defense systems . In: Curr. Opin. Cell Biol . 3, No. 4, 1991, pp. 710-6. doi : 10.1016 / 0955-0674 (91) 90045-Z . PMID 1722985 .
  2. ↑ Tschopp J, Masson D, Stanley KK: Structural / functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis . In: Nature . 322, No. 6082, 1986, pp. 831-4. doi : 10.1038 / 322831a0 . PMID 2427956 .
  3. ↑ a b Voskoboinik I, Smyth MJ, Trapani JA: Perforin-mediated target-cell death and immune homeostasis . In: Nat. Rev. Immunol. . 6, No. 12, 2006, pp. 940-52. doi : 10.1038 / nri1983 . PMID 17124515 .
  4. ↑ Kaiserman D, Bird CH, Sun J, et al. : The major human and mouse granzymes are structurally and functionally divergent . In: J. Cell Biol. . 175, No. 4, 2006, pp. 619-30. doi : 10.1083 / jcb.200606073 . PMID 17116752 . PMC 2064598 (free full text).
  5. ↑ a b Voskoboinik I, Sutton VR, Ciccone A, et al. : Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function . In: Blood . 110, No. 4, 2007, pp. 1184-90. doi : 10.1182 / blood-2007-02-072850 . PMID 17475905 .
  6. ↑ Witzel-Schlömp K, Späth PJ, Hobart MJ, et al. : The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure . In: J. Immunol. . 158, No. 10, 1997, pp. 5043-9. PMID 9144525 .
  7. ↑ a b c d e f g Rosado CJ, Buckle AM, Law RH, et al. : A Common Fold Mediates Vertebrate Defense and Bacterial Attack . In: Science . 317, No. 5844, 2007, pp. 1548-1551. doi : 10.1126 / science.1144706 . PMID 17717151 .
  8. ↑ Michael A. Hadders, Dennis X. Beringer, and Piet Gros: Structure of C8-MACPF Reveals Mechanism of Membrane Attack in Complement Immune Defense . In: Science . 317, No. 5844, 2007, pp. 1552-1554. doi : 10.1126 / science.1147103 . PMID 17872444 .
  9. ↑ Morita-Yamamuro C, Tsutsui T, Sato M, et al. : The Arabidopsis gene CAD1 controls programmed cell death in the plant immune system and encodes a protein containing a MACPF domain . In: Plant Cell Physiol. . 46, No. 6, 2005, pp. 902-12. doi : 10.1093 / pcp / pci095 . PMID 15799997 .
  10. ↑ Oshiro N, Kobayashi C, Iwanaga S, et al. : A new membrane-attack complex / perforin (MACPF) domain lethal toxin from the nematocyst venom of the Okinawan sea anemone Actineria villosa . In: Toxicon . 43, No. 2, 2004, pp. 225-8. doi : 10.1016 / j.toxicon.2003.11.017 . PMID 15019483 .
  11. ↑ Kadota K, Ishino T, Matsuyama T, Chinzei Y, Yuda M: Essential role of membrane-attack protein in malarial transmission to mosquito host . In: Proc. Natl. Acad. Sci. USA . 101, No. 46, 2004, pp. 16310-5. doi : 10.1073 / pnas.0406187101 . PMID 15520375 . PMC 524694 (free full text).
  12. ↑ 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 . In: Cell. Microbiol. . 7, No. 2, 2005, pp. 199-208. doi : 10.1111 / j.1462-5822.2004.00447.x . PMID 15659064 .
  13. ↑ Zheng C, Heintz N, Hatten ME: CNS gene encoding astrotactin, which supports neuronal migration along glial fibers . In: Science . 272, No. 5260, 1996, pp. 417-9. doi : 10.1126 / science.272.5260.417 . PMID 8602532 .
  14. ↑ Haag ES, Sly BJ, Andrews ME, Raff RA: Apextrin, a novel extracellular protein associated with larval ectoderm evolution in Heliocidaris erythrogramma . In: Dev. Biol. . 211, No. 1, 1999, pp. 77-87. doi : 10.1006 / dbio.1999.9283 . PMID 10373306 .
  15. ↑ Martin JR, Raibaud A, Ollo R: Terminal pattern elements in Drosophila embryo induced by the torso-like protein . In: Nature . 367, No. 6465, 1994, pp. 741-5. doi : 10.1038 / 367741a0 . PMID 8107870 .
  16. ^ Ponting CP: Chlamydial homologues of the MACPF (MAC / perforin) domain . In: Curr. Biol . 9, No. 24, 1999, pp. R911-3. doi : 10.1016 / S0960-9822 (00) 80102-5 . PMID 10608922 .
  17. ↑ Michael A. Hadders, Dennis X. Beringer, and Piet Gros: Structure of C8-MACPF Reveals Mechanism of Membrane Attack in Complement Immune Defense . In: Science . 317, No. 5844, 2007, pp. 1552-1554. doi : 10.1126 / science.1147103 . PMID 17872444 .
  18. ↑ Rossjohn J, Feil SC, McKinstry WJ, Tweten RK, Parker MW: Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form . In: Cell . 89, No. 5, 1997, pp. 685-92. doi : 10.1016 / S0092-8674 (00) 80251-2 . PMID 9182756 .
  19. ↑ Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR: Structural basis of pore formation by the bacterial toxin pneumolysin . In: Cell . 121, No. 2, 2005, pp. 247-56. doi : 10.1016 / j.cell.2005.02.033 . PMID 15851031 .
  20. ↑ Kieffer B, Driscoll PC, Campbell ID, Willis AC, van der Merwe PA, Davis SJ: Three-dimensional solution structure of the extracellular region of the complement regulatory protein CD59, a new cell-surface protein domain related to snake venom neurotoxins . In: Biochemistry . 33, No. 15, 1994, pp. 4471-82. doi : 10.1021 / bi00181a006 . PMID 7512825 .
  21. ↑ 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 . In: Molecular Immunology . 45, No. 3, 2007, pp. 750-6. doi : 10.1016 / j.molimm.2007.06.359 . PMID 17692377 .
  22. ↑ 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 . In: Hum. Genet. . 102, No. 6, 1998, pp. 605-10. doi : 10.1007 / s004390050749 . PMID 9703418 .
  23. ↑ Mark J. Walport : Complement. First of two parts . In: N. Engl. J. Med. . 344, No. 14, 2001, pp. 1058-66. doi : 10.1056 / NEJM200104053441406 . PMID 11287977 .
  24. ↑ Verbsky JW, Grossman WJ: hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives . In: Ann. Med. . 38, No. 1, 2006, pp. 20-31. doi : 10.1080 / 07853890500465189 . PMID 16448985 .
  25. ^ Wright KO, Messing EM, Reeder JE: DBCCR1 mediates death in cultured bladder tumor cells . In: Oncogene . 23, No. 1, 2004, pp. 82-90. doi : 10.1038 / sj.onc.1206642 . PMID 14712213 .