Pore-forming toxins (PFTs) are commonly associated with bacterial and other prokaryote pathogenesis. In eukaryotes, PFTs play important roles in immunity, embryonic development and neural-cell migration. Two families of globular protein PFTs: the cholesterol-dependent cytolysins (CDCs) and the membrane attack complex/perforin superfamily (MACPF), arrest researchers’ attention due to their unique molecular configuration and the function. CDCs are produced by Gram-positive bacteria and disrupt the membrane of host cells during infection. In eukaryotes, MACPF proteins have both lytic and non-lytic roles. With perfringolysin O (PFO) for example, the structure and molecular mechanism of CDCs are relatively well characterized. Recently crystallographic together with biochemical studies revealed that although MACPF and CDCs were extremely divergent at the amino acid sequence level, their common fold suggests that lytic MACPF proteins use a CDC-like mechanism of membrane disruption. This paper focuses on the structure, molecular mechanism of pore-formation and the research hotspot of the two families of PFTs, providing valuable clues for the future research in this field.
[1] Nagai H, Oshiro N, Takuwa-Kuroda K, Iwanaga S, Nozaki M, Nakajima T. Novel proteinaceous toxins from the nematocyst venom of the Okinawan sea anemone Phyl-lodiscus semoni Kwietniewski. Biochem Biophys Res Commun, 2002, 294(4): 760–763.
[2] Parker MW, Feil SC. Pore-forming protein toxins: from structure to function. Prog Biophys Mol Biol, 2005, 88(1): 91–142.
[3] Aroian R, van der Goot FG. Pore-forming toxins and cel-lular non-immune defenses (CNIDs). Curr Opin Microbiol, 2007, 10(1): 57–61.
[4] van der Goot G (Ed). Pore-forming toxins In: Current Topics in Microbiology and Immunology, 1st edition. Springer Verlag, Berlin Heidelberg, 2001.
[5] Balachandran P, Hollingshead SK, Paton JC, Briles DE. The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J Bacteriol, 2001, 183(10): 3108–3116.
[6] Rosado CJ, Kondos S, Bull TE, Kuiper MJ, Law RHP, Buckle AM, Voskoboinik I, Bird PI, Trapani JA, Whisstock JC, Dunstone MA. The MACPF/CDC family of pore-forming toxins. Cell Microbiol, 2008, 10(9): 1765–1774.
[7] Gonzalez MR, Bischofberger M, Pernot L, van der Goot FG, Frêche B. Bacterial pore-forming toxins: the (w)hole story? Cell Mol Life Sci, 2008, 65(3): 493–507.
[8] Soltani CE, Hotze EM, Johnson AE, Tweten RK. Specific protein-membrane contacts are required for prepore and pore assembly by a cholesterol-dependent cytolysin. J Biol Chem, 2007, 282(21): 15709–15716.
[9] Soltani CE, Hotze EM, Johnson AE, Tweten RK. Struc-tural elements of the cholesterol-dependent cytolysins that are responsible for their cholesterol-sensitive membrane interactions. Proc Natl Acad Sci USA, 2007, 104(51): 20226–20231.
[10] Rosado CJ, Buckle AM, Law RHP, Butcher RE, Kan WT, Bird CH, Ung K, Browne KA, Baran K, Bash-tannyk-Puhalovich TA, Faux NG, Wong W, Porter CJ, Pike RN, Ellisdon AM, Pearce MC, Bottomley SP, Emsley J, Smith AI, Rossjohn J, Hartland EL, Voskoboinik I, Tra-pani JA, Bird PI, Dunstone MA, Whisstock JC. A common fold mediates vertebrate defense and bacterial attack. Science, 2007, 317(5844): 1548–1551.
[11] Lukoyanova N, Saibil HR. Friend or foe: the same fold for attack and defense. Trends Immunol, 2008, 29(2): 51–53.
[12] Slade DJ, Lovelace LL, Chruszcz M. Crystal structure of the MACPF domain of human complement protein C8α in complex with the C8γ subunit. J Mol Biol, 2008, 379(2): 331–342.
[13] Watson NFS, Durrant LG, Madjd Z, Ellis IO, Scholefield JH, Spendlove I. Expression of the membrane complement regulatory protein CD59 (protectin) is associated with re-duced survival in colorectal cancer patients. Cancer Immunol Immunother, 2006, 55(8): 973–980.
[14] Harhausen D, Khojasteh U, Stahel PF, Morgan BP, Niet-feld W, Dirnagl U, Trendelenburg G. Membrane attack complex inhibitor CD59a protects against focal cerebral ischemia in mice. J Neuroinflamm , 2010, 7: 15.
[15] Uellner R, Zvelebil MJ, Hopkins J, Jones J, MacDougall LK, Morgan BP, Podack E, Waterfield MD, Griffiths GM. Perforin is activated by a proteolytic cleavage during bio-synthesis which reveals a phospholipid-binding C2 do-main. EMBO J, 1997, 16(24): 7287–7296.
[16] Voskoboinik I, Thia MC, Fletcher J, Ciccone A, Browne K, Smyth MJ, Trapani JA. Calcium-dependent plasma mem-brane binding and cell lysis by perforin are mediated through its C2 domain: A critical role for aspartate resi-dues 429, 435, 483, and 485 but not 491. J Biol Chem, 2005, 280(9): 8426–8434.
[17] Bolitho P, Voskoboinik I, Trapani JA, Smyth MJ. Apop-tosis induced by the lymphocyte effector molecule per-forin. Curr Opin Immunol, 2007, 19(3): 339–347.
[18] Pipkin ME, Lieberman J. Delivering the kiss of death: progress on understanding how perforin works. Curr Opin Immunol, 2007, 19(3): 301&nd
