Symbol = MACPF
Name = MAC/Perforin domain

width =
caption =
Pfam= PF01823
InterPro= IPR001862
TCDB = 1.C.39
OPM family=
OPM protein=

The MACPF protein superfamily is named after a domain that is common to the Membrane Attack Complex proteins (MAC) of complement (C6, C7, C8α, C8β and C9) and perforin (PF). Many members of this protein family are important eukaryote pore forming toxins. [cite journal |author=Peitsch MC, Tschopp J |title=Assembly of macromolecular pores by immune defense systems |journal=Curr. Opin. Cell Biol. |volume=3 |issue=4 |pages=710–6 |year=1991 |pmid=1722985 |doi=]

The archetypal members of the family are complement C9 and perforin, both of which function in human immunity [cite journal |author=Tschopp J, Masson D, Stanley KK |title=Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis |journal=Nature |volume=322 |issue=6082 |pages=831–4 |year=1986 |pmid=2427956 |doi=10.1038/322831a0] . C9 functions by punching holes in the membrane of pathogenic 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 granyzmes that cause cell death. [cite journal |author=Voskoboinik I, Smyth MJ, Trapani JA |title=Perforin-mediated target-cell death and immune homeostasis |journal=Nat. Rev. Immunol. |volume=6 |issue=12 |pages=940–52 |year=2006 |pmid=17124515 |doi=10.1038/nri1983] Deficiency of either protein can result in human disease.cite journal |author=Voskoboinik I, Sutton VR, Ciccone A, "et al" |title=Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function |journal=Blood |volume=110 |issue=4 |pages=1184–90 |year=2007 |pmid=17475905 |doi=10.1182/blood-2007-02-072850] [cite journal |author=Witzel-Schlömp K, Späth PJ, Hobart MJ, "et al" |title=The human complement C9 gene: identification of two mutations causing deficiency and revision of the gene structure |journal=J. Immunol. |volume=158 |issue=10 |pages=5043–9 |year=1997 |pmid=9144525 |doi=] 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. [cite journal |title=Structure of C8-MACPF Reveals Mechanism of Membrane Attack in Complement Immune Defense |author=Michael A. Hadders, Dennis X. Beringer, and Piet Gros |journal=Science |doi=10.1126/science.1147103 |pages=1552–1554 |year=2007 |volume=317]

Biological roles of MACPF domain containing proteins

To date, around 500 members of the MACPF superfamily have been identified. Many of these proteins play key roles in the plant and animal immunity.

The 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 granyzmes A and B into target cells. Once delivered, granyzmes are able to induce apoptosis and cause target cell death. [cite journal |author=Voskoboinik I, Smyth MJ, Trapani JA |title=Perforin-mediated target-cell death and immune homeostasis |journal=Nat. Rev. Immunol. |volume=6 |issue=12 |pages=940–52 |year=2006 |pmid=17124515 |doi=10.1038/nri1983] [cite journal |author=Kaiserman D, Bird CH, Sun J, "et al" |title=The major human and mouse granzymes are structurally and functionally divergent |journal=J. Cell Biol. |volume=175 |issue=4 |pages=619–30 |year=2006 |pmid=17116752 |doi=10.1083/jcb.200606073]

The plant protein CAD1 functions in the plant immune response to bacterial infection. [cite journal |author=Morita-Yamamuro C, Tsutsui T, Sato M, "et al" |title=The Arabidopsis gene CAD1 controls programmed cell death in the plant immune system and encodes a protein containing a MACPF domain |journal=Plant Cell Physiol. |volume=46 |issue=6 |pages=902–12 |year=2005 |pmid=15799997 |doi=10.1093/pcp/pci095]

The sea anemone "Actineria villosa" uses a MACPF protein as a lethal toxin. [cite journal |author=Oshiro N, Kobayashi C, Iwanaga S, "et al" |title=A new membrane-attack complex/perforin (MACPF) domain lethal toxin from the nematocyst venom of the Okinawan sea anemone Actineria villosa |journal=Toxicon |volume=43 |issue=2 |pages=225–8 |year=2004 |pmid=15019483 |doi=10.1016/j.toxicon.2003.11.017] MACPF proteins are also important for the invasion of the Malarial parasite into the mosquito host and the liver. [cite journal |author=Kadota K, Ishino T, Matsuyama T, Chinzei Y, Yuda M |title=Essential role of membrane-attack protein in malarial transmission to mosquito host |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=101 |issue=46 |pages=16310–5 |year=2004 |pmid=15520375 |doi=10.1073/pnas.0406187101] [cite journal |author=Ishino T, Chinzei Y, Yuda M |title=A Plasmodium sporozoite protein with a membrane attack complex domain is required for breaching the liver sinusoidal cell layer prior to hepatocyte infection |journal=Cell. Microbiol. |volume=7 |issue=2 |pages=199–208 |year=2005 |pmid=15659064 |doi=10.1111/j.1462-5822.2004.00447.x]

Not all MACPF proteins function in defence or attack. For example, astrotactin is involved in neural cell migration in mammals and apextrin is involved in sea urchin ("Heliocidaris erythrogramma") development. [cite journal |author=Zheng C, Heintz N, Hatten ME |title=CNS gene encoding astrotactin, which supports neuronal migration along glial fibers |journal=Science |volume=272 |issue=5260 |pages=417–9 |year=1996 |pmid=8602532 |doi=] [cite journal |author=Haag ES, Sly BJ, Andrews ME, Raff RA |title=Apextrin, a novel extracellular protein associated with larval ectoderm evolution in Heliocidaris erythrogramma |journal=Dev. Biol. |volume=211 |issue=1 |pages=77–87 |year=1999 |pmid=10373306 |doi=10.1006/dbio.1999.9283] "Drosophila" Torso-like protein, which controls embryonic patterning [cite journal |author=Martin JR, Raibaud A, Ollo R |title=Terminal pattern elements in Drosophila embryo induced by the torso-like protein |journal=Nature |volume=367 |issue=6465 |pages=741–5 |year=1994 |pmid=8107870 |doi=10.1038/367741a0] , also contains a MACPF domain. It is unknown whether the function of any of these proteins involves lytic activity.

Functionally uncharacterised MACPF proteins are sporadically distributed in bacteria. Several species of "Chlamydia" contain MACPF proteins. [cite journal |author=Ponting CP |title=Chlamydial homologues of the MACPF (MAC/perforin) domain |journal=Curr. Biol. |volume=9 |issue=24 |pages=R911–3 |year=1999 |pmid=10608922 |doi=] The insect pathogenic bacteria "Photorhabdus luminescens" also contains a MACPF protein, however, this molecule appears non-lytic.

tructure and mechanism

The X-ray crystal structure of Plu-MACPF, a protein from the insect pathogenic enterobacteria "Photorhabdus luminescens" has been determined (figure 1). [] 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 sequnce based data mining techniques.

It is suggested that MACPF proteins and CDCs form pores in the same way (figure 1). 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. Like CDC's MACPF proteins are thus β-pore forming toxins that act like a molecular hole punch.

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. [cite journal |author=Huang Y, Qiao F, Abagyan R, Hazard S, Tomlinson S |title=Defining the CD59-C9 binding interaction |journal=J. Biol. Chem. |volume=281 |issue=37 |pages=27398–404 |year=2006 |pmid=16844690 |doi=10.1074/jbc. M603690200] [cite journal |author=Lockert DH, Kaufman KM, Chang CP, Hüsler T, Sodetz JM, Sims PJ |title=Identity of the segment of human complement C8 recognized by complement regulatory protein CD59 |journal=J. Biol. Chem. |volume=270 |issue=34 |pages=19723–8 |year=1995 |pmid=7544344 |doi=] 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.

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. [cite journal |author=Schreck SF, Plumb ME, Platteborze PL, "et al" |title=Expression and characterization of recombinant subunits of human complement component C8: further analysis of the function of C8 alpha and C8 gamma |journal=J. Immunol. |volume=161 |issue=1 |pages=311–8 |year=1998 |pmid=9647238 |doi=] cite journal |author=Lovelace LL, Chiswell B, Slade DJ, Sodetz JM, Lebioda L |title=Crystal structure of complement protein C8gamma in complex with a peptide containing the C8gamma binding site on C8alpha: Implications for C8gamma ligand binding |journal= |volume= |issue= |pages= |year=2007 |pmid=17692377 |doi=10.1016/j.molimm.2007.06.359]

Role in Human disease

Deficiency of C9, or other components of the MAC results in an increased susceptibity to diseases caused by Gram negative bacteria such as meningococcal meningitis. [cite journal |author=Kira R, Ihara K, Takada H, Gondo K, Hara T |title=Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency |journal=Hum. Genet. |volume=102 |issue=6 |pages=605–10 |year=1998 |pmid=9703418 |doi=] 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. [cite journal |author=Walport MJ |title=Complement. First of two parts |journal=N. Engl. J. Med. |volume=344 |issue=14 |pages=1058–66 |year=2001 |pmid=11287977 |doi=]

Perforin deficiency results in the commonly fatal disorder familial hemophagocytic lymphohistiocytosis (FHL or HLH). This disease is characterised by an overactivation of lymphocytes which results in cytokine mediated organ damage. [cite journal |author=Verbsky JW, Grossman WJ |title=Hemophagocytic lymphohistiocytosis: diagnosis, pathophysiology, treatment, and future perspectives |journal=Ann. Med. |volume=38 |issue=1 |pages=20–31 |year=2006 |pmid=16448985 |doi=10.1080/07853890500465189]

The MACPF protein DBCCR1 may function as a tumour suppressor in bladder cancer. [cite journal |author=Wright KO, Messing EM, Reeder JE |title=DBCCR1 mediates death in cultured bladder tumor cells |journal=Oncogene |volume=23 |issue=1 |pages=82–90 |year=2004 |pmid=14712213 |doi=10.1038/sj.onc.1206642]

Human proteins containing this domain

C6; C7; C8A; C8B; C9; FAM5B; FAM5C; MPEG1;

ee also

*pore forming toxin
*Membrane attack complex


External links

* [ James Whisstock's laboratory] at Monash University
* [ Phil Bird's laboratory] at Monash University
* [ Joe Trapani's laboratory] at the Peter MacCallum Cancer Institute
* [ James Sodetz laboratory] at the University of South Carolina
* [ The SMART MACPF protein family page]
* [ The pfam MACPF protein family page]
* [ Ethan Michael Smith Foundation provides information for people with HLH and related disorders]
* [ The Histiocytosis Association of America]
* [ The Histiocytosis Research Trust in the UK]

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