1.C.12 The Thiol-activated Cholesterol-dependent Cytolysin (CDC) Family

Cholesterol-binding 'sulfhydryl-activated' toxins bind to cholesterol containing animal cell membranes and can be reversibly inactivated by oxidation. The prototype of the family, perfringolysin O (PFO), can lyse cholesterol-containing membranes of eukaryotic host cells. Cholesterol is the receptor for toxin binding, and following binding, the proteolytically processed subunits oligomerize to form the integral membrane, pore-forming, ring-shaped structure. Structural data for perfringolysin O are available, and a model for its membrane-associated form has been proposed. The oligomeric state of Pneumolysin involves 30-50 monomers complexed with lipid (Boney et al., 2001). Christie et al. 2018 presented an overview of the known features of the structures and functions of the CDCs, including the structure of the secreted monomers, the process of interaction with target membranes, and the transition from bound monomers to complete pores.

One CDC family member, Listeriolysin O (1.C.12.1.7), is produced by the intracellular parasite, Listeria monocytogenes. This pore-forming toxin contains a Pro-Glu-Ser-Thr (PEST) sequence that is essential for virulence and intracellular compartmentalization to the cytosol. Without the PEST sequence, the host cell is killed. Listerolysin O is probably targeted for degradation due to the presence of the PEST sequence. Thus, the PEST sequence converts the toxic cytolysin into a nontoxic derivative that allows intracelluar growth (Decatur and Portnoy, 2000). Listeriolysin O mediates lysis of L. monoctogenes-containing phagosomes and also facilitates cell-to-cell spreading (Dancz et al., 2002). Thus, it is bifunctional, but both functions probably depend on its pore-forming activity.

Pore-forming toxins of the CDC family allow delivery of macromolecules of up to 100 kDa to the host cell cytoplasm in a fully folded native conformation (Gonzalez et al., 2008). The large pores formed may contain up to 50 subunits. The animal cell receptors of many bacterial toxins have been tabulated by Gonzelez et al. (Gonzelez et al. 2008). Streptolysin O-permeabilized cells can be resealed by the action of Ca2+-calmodulin plus microtubules. CDC family toxins may thus serve to deliver proteins to the host cell cytoplasm, and they can be useful for artificial delivery of macromolecules to animal cells in general (Walev et al., 2001).

At the level of the primary structure, cholesterol dependent cytolysins (CDCs) display a high degree of sequence similarity ranging from 40% to 80%. This is mainly reflected in the conserved core of about 471 amino acids shared by all CDCs, which essentially corresponds to the sequence of pneumolysin, the shortest member of the family (Gonzalez et al., 2008). CDCs with longer sequences usually display variations in the N terminus, the functions of which are unknown for many members. Furthermore, all CDCs contain a highly conserved undecapeptide, which is thought to be critical for cholesterol-mediated membrane recognition. CDCs indeed all share a strict cholesterol dependency for oligomerization, which gave them their name. Most CDCs seem to use choletserol directly as a receptor. Intermedilysin (ILY) from Streptococcus intermedius, however, was shown to have a proteinaceous receptor, i.e., the GPI-anchored protein CD59 (Gonzalez et al., 2008). Interestingly, ILY shows a lower degree of conservation in the conserved undecapeptide important for cholesterol binding. As for all CDCs, pore formation by ILY requires the presence of choletserol for the membrane insertion step.

As noted above, the water-soluble monomeric cytolysin, perfringolysin O (PFO), secreted by Clostridium perfringens, oligomerizes and forms large pores upon encountering cholestrol-containing membranes. These pores, composed of 40-80 monomers, are large enough (15-30 nm diameter) to allow passage of macromolecules. Cysteine-scanning mutagenesis and multiple independent fluorescence techniques have suggested that each PFO monomer containing four domains, one of which is primarily involved in pore formation and has two amphipathic β-hairpins that span the membrane. In the soluble monomer, these transmembrane segments are folded into six α-helices (Shatursky et al., 1999; Billington et al., 2000). The insertion of two transmembrane hairpins per toxin monomer and a major change in secondary structure (vertical collapse) define a novel paradigm for the mechanism of membrane insertion by a cytolytic toxin (Czajkowsky et al., 2004).

The structural basis of Pneumolysin (1.C.12.1.5) has been presented (Tilley et al., 2005). As for other members of the CDC family, it is released from the bacterial cell as a monomer and assembles into large oligomeric rings in the target cell plasma membrane. Using cryoelectron microscopy and image processing, Tilley et al. have determined the structures of membrane-surface bound (prepore) and inserted-pore oligomer forms, providing a direct observation of the conformational transition into the pore form of a cholesterol-dependent cytolysin. In the pore structure, the domains of the monomer separate and double over into an arch, forming a wall sealing the bilayer around the pore. This transformation is accomplished by substantial refolding of two of the four protein domains along with deformation of the membrane. Extension of protein density into the bilayer supports earlier predictions that the protein inserts β-hairpins into the membrane. With an oligomer size of up to 44 subunits in the pore, this assembly creates a transmembrane channel 260 Å in diameter lined by 176 β-strands.

Despite their designation as 'thiol-activated' cytolysins, thiol activation does not appear to be a physiologically important property of these toxins. These proteins have therefore been renamed 'cholesterol-dependent cytolysins' (CDC). A detailed analysis of membrane interactive structures at the tip of perfringolysin O (PFO) domain 4 reveals that a threonine-leucine pair mediates CDC recognition of and binding to membrane cholesterol. This motif is conserved in all known CDCs, and conservative changes in its sequence or order are not well tolerated. Thus, the Thr-Leu pair mediates CDC-cholesterol recognition and binding (Farrand et al., 2010).

CDCs form large β-barrel pore complexes that are assembled from 35 to 40 soluble CDC monomers. Pore formation is dependent on the presence of membrane cholesterol, which functions as the receptor for most CDCs. Cholesterol binding initiates significant secondary and tertiary structural changes in the monomers, which lead to the assembly of a large membrane embedded β-barrel pore complex. The molecular mechanism of assembly of the CDC membrane pore complex has been reviewed (Hotze and Tweten, 2011). 

As noted above, membrane-bound oligomers assemble into a prepore oligomeric form, following which the prepore assembly collapses towards the membrane surface, with concomitant release and insertion of the membrane spanning subunits (Reboul et al. 2014). During this rearrangement it is proposed that Domain 2, a region comprising three β-strands that links the pore forming region (Domains 1 and 3) and the Ig domain, must undergo a significant conformational change. Simple rigid body rotations may account for the observed collapse of the prepore towards the membrane surface.  Domains 1, 2 and 4 are able to undergo significant rotational movements with respect to each other (Reboul et al. 2014).

 

The generalized transport reaction catalyzed by CDC family members is:

small and large molecules (in) → small and large molecules (out).



This family belongs to the MACPF Superfamily.

 

References:

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Anderson, R., J.G. Nel, and C. Feldman. (2018). Multifaceted Role of Pneumolysin in the Pathogenesis of Myocardial Injury in Community-Acquired Pneumonia. Int J Mol Sci 19:.

Balachandran, P., S.K. Hollingshead, J.C. Paton, and D.E. Briles. (2001). The autolytic enzyme LytA of Streptococcus pneumoniae is not responsible for releasing pneumolysin. J. Bacteriol. 183: 3108-3116.

Baruch, M., I. Belotserkovsky, B.B. Hertzog, M. Ravins, E. Dov, K.S. McIver, Y.S. Le Breton, Y. Zhou, C.Y. Chen, and E. Hanski. (2014). An extracellular bacterial pathogen modulates host metabolism to regulate its own sensing and proliferation. Cell 156: 97-108.

Billington, S.J., B.H. Jost, and J.G. Songer. (2000). Thiol-activated cytolysins: structure, function and role in pathogenesis. FEMS Microbiol. 182: 197-205.

Bonev, B.B., R.J.C. Gilbert, P.W. Andrew, O. Byron, and A. Watts. (2001). Strucural analysis of the protein/lipid complexes associated with pore formation by the bacterial toxin pneumolysin. J. Biol. Chem. 276: 5714-5719.

Boyd, C.M., E.S. Parsons, R.A. Smith, J.M. Seddon, O. Ces, and D. Bubeck. (2016). Disentangling the roles of cholesterol and CD59 in intermedilysin pore formation. Sci Rep 6: 38446.

Christie, M.P., B.A. Johnstone, R.K. Tweten, M.W. Parker, and C.J. Morton. (2018). Cholesterol-dependent cytolysins: from water-soluble state to membrane pore. Biophys Rev 10: 1337-1348.

Czajkowsky, D.M., E.M. Hotze, Z. Shao, and R.K. Tweten. (2004). Vertical collapse of a cytolysin prepore moves its transmembrane β-hairpins to the membrane. EMBO J. 23: 3206-3215.

Dancz, C.E., A. Haraga, D.A. Portnoy, and D.E. Higgins. (2002). Inducible control of virulence gene expression in Listeria monocytogenes: Temporal requirement of Listeriolysin O during intracellular infection. J. Bacteriol. 184: 5935-5945.

Decatur, A.L. and D.A. Portnoy. (2000). A PEST-like sequence in Listerolysin-O essential for Listeria monocytogenes pathogenicity. Science. 290: 992-995.

Domon, H., T. Maekawa, D. Yonezawa, K. Nagai, M. Oda, K. Yanagihara, and Y. Terao. (2018). Mechanism of Macrolide-Induced Inhibition of Pneumolysin Release Involves Impairment of Autolysin Release in Macrolide-Resistant Streptococcus pneumoniae. Antimicrob. Agents Chemother. 62:.

El-Rachkidy, R.G., N.W. Davies, and P.W. Andrew. (2008). Pneumolysin generates multiple conductance pores in the membrane of nucleated cells. Biochem. Biophys. Res. Commun. 368: 786-792.

Farrand, A.J., S. LaChapelle, E.M. Hotze, A.E. Johnson, and R.K. Tweten. (2010). Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface. Proc. Natl. Acad. Sci. USA 107: 4341-4346.

Gauthier, A. and B.B. Finlay. (2001). Bacterial pathogenesis: the answer to virulence is in the pore. Curr. Biol. 11: R264-R267.

Gonzalez, M.R., M. Bischofberger, L. Pernot, F.G. van der Goot, and B. Frêche. (2008). Bacterial pore-forming toxins: the (w)hole story? Cell. Mol. Life Sci. 65: 493-507.

Heuck, A.P., C.G. Savva, A. Holzenburg, and A.E. Johnson. (2007). Conformational changes that effect oligomerization and initiate pore formation are triggered throughout perfringolysin O upon binding to cholesterol. J. Biol. Chem. 282: 22629-22637.

Hotze EM. and Tweten RK. (2012). Membrane assembly of the cholesterol-dependent cytolysin pore complex. Biochim Biophys Acta. 1818(4):1028-38.

Johnson, B.B. and A.P. Heuck. (2014). Perfringolysin o structure and mechanism of pore formation as a paradigm for cholesterol-dependent cytolysins. Subcell Biochem 80: 63-81.

Kacprzyk-Stokowiec A., Kulma M., Traczyk G., Kwiatkowska K., Sobota A. and Dadlez M. (2014). Crucial role of perfringolysin O D1 domain in orchestrating structural transitions leading to membrane-perforating pores: a hydrogen-deuterium exchange study. J Biol Chem. 289(41):28738-52.

Kulma, M., A. Kacprzyk-Stokowiec, G. Traczyk, K. Kwiatkowska, and M. Dadlez. (2019). Fine-tuning of the stability of β-strands by Y181 in perfringolysin O directs the prepore to pore transition. Biochim. Biophys. Acta. Biomembr 1861: 110-122.

LaChapelle, S., R.K. Tweten, and E.M. Hotze. (2009). Intermedilysin-receptor interactions during assembly of the pore complex: assembly intermediates increase host cell susceptibility to complement-mediated lysis. J. Biol. Chem. 284: 12719-12726.

Lacy, D.B. and R.C. Stevens. (1998). Unraveling the structures and modes of action of bacterial toxins. Curr. Opin. Struc. Biol. 8: 778-784.

Lin Q., Wang T., Li H. and London E. (2015). Decreasing Transmembrane Segment Length Greatly Decreases Perfringolysin O Pore Size. J Membr Biol. 248(3):517-27.

Lin, Q. and E. London. (2014). The Influence of Natural Lipid Asymmetry upon the Conformation of a Membrane-inserted Protein (Perfringolysin O). J. Biol. Chem. 289: 5467-5478.

Malet, J.K., P. Cossart, and D. Ribet. (2016). Alteration of epithelial cell lysosomal integrity induced by bacterial cholesterol-dependent cytolysins. Cell Microbiol. [Epub: Ahead of Print]

Meehl, M.A. and M.G. Caparon. (2004). Specificity of streptolysin O in cytolysin-mediated translocation. Mol. Microbiol. 52: 1665-1676.

Mulvihill E., van Pee K., Mari SA., Muller DJ. and Yildiz O. (2015). Directly Observing the Lipid-Dependent Self-Assembly and Pore-Forming Mechanism of the Cytolytic Toxin Listeriolysin O. Nano Lett. 15(10):6965-73.

Podobnik, M., M. Marchioretto, M. Zanetti, A. Bavdek, M. Kisovec, M.M. Cajnko, L. Lunelli, M. Dalla Serra, and G. Anderluh. (2015). Plasticity of Lysteriolysin O Pores and its Regulation by pH and Unique Histidine. Sci Rep 5: 9623.

Price, K.E. and A. Camilli. (2009). Pneumolysin localizes to the cell wall of Streptococcus pneumoniae. J. Bacteriol. 191: 2163-2168.

Radtke, A.L., K.L. Anderson, M.J. Davis, M.J. DiMagno, J.A. Swanson, and M.X. O'Riordan. (2011). Listeria monocytogenes exploits cystic fibrosis transmembrane conductance regulator (CFTR) to escape the phagosome. Proc. Natl. Acad. Sci. USA 108: 1633-1638.

Ramarao, N. and V. Sanchis. (2013). The pore-forming haemolysins of bacillus cereus: a review. Toxins (Basel) 5: 1119-1139.

Reboul, C.F., J.C. Whisstock, and M.A. Dunstone. (2014). A new model for pore formation by cholesterol-dependent cytolysins. PLoS Comput Biol 10: e1003791.

Rossjohn, J., S.C. Feil, W.J. McKinstry, R.K. Tweten, and M.W. Parker. (1997). Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form. Cell 89: 685-692.

Rzewuska, M., E. Kwiecień, D. Chrobak-Chmiel, M. Kizerwetter-Świda, I. Stefańska, and M. Gieryńska. (2019). Pathogenicity and Virulence of : A Review. Int J Mol Sci 20:.

Sarangi, N.K., I.I. P, K.G. Ayappa, S.S. Visweswariah, and J.K. Basu. (2016). Super-resolution Stimulated Emission Depletion-Fluorescence Correlation Spectroscopy Reveals Nanoscale Membrane Reorganization Induced by Pore-Forming Proteins. Langmuir 32: 9649-9657.

Savinov, S.N. and A.P. Heuck. (2017). Interaction of Cholesterol with Perfringolysin O: What Have We Learned from Functional Analysis? Toxins (Basel) 9:.

Schuerch, D.W., E.M. Wilson-Kubalek, and R.K. Tweten. (2005). Molecular basis of listeriolysin O pH dependence. Proc. Natl. Acad. Sci. USA 102: 12537-12542.

Shatursky, O., A.P. Heuck, L.A. Shepard, J. Rossjohn, M.W. Parker, A.E. Johnson, and R.K. Tweten. (1999). The mechanism of membrane insertion for a cholesterol-dependent cytolysin: A novel paradigm for pore-forming toxins. Cell 99: 293-299.

Skariyachan, S., N. Prakash, and N. Bharadwaj. (2012). In silico exploration of novel phytoligands against probable drug target of Clostridium tetani. Interdiscip Sci 4: 273-281.

Song, M., L. Li, M. Li, Y. Cha, X. Deng, and J. Wang. (2016). Apigenin protects mice from pneumococcal pneumonia by inhibiting the cytolytic activity of pneumolysin. Fitoterapia 115: 31-36. [Epub: Ahead of Print]

Tenenbaum, T., M. Seitz, H. Schroten, and C. Schwerk. (2016). Biological activities of suilysin: role in Streptococcus suis pathogenesis. Future Microbiol 11: 941-954.

Tilley, S.J. and H.R. Saibil. (2006). The mechanism of pore formation by bacterial toxins. Curr. Opin. Struct. Biol. 16: 230-236.

Tilley, S.J., E.V. Orlova, R.J. Gilbert, P.W. Andrew, and H.R. Saibil. (2005). Structural basis of pore formation by the bacterial toxin pneumolysin. Cell 121: 247-256.

van Pee, K., E. Mulvihill, D.J. Müller, and &.#.2.1.4.;. Yildiz. (2016). Unraveling the Pore-Forming Steps of Pneumolysin from Streptococcus pneumoniae. Nano Lett. [Epub: Ahead of Print]

Viala, J.P., S.N. Mochegova, N. Meyer-Morse, and D.A. Portnoy. (2008). A bacterial pore-forming toxin forms aggregates in cells that resemble those associated with neurodegenerative diseases. Cell Microbiol 10(4): 985-993.

Vögele, M., R.M. Bhaskara, E. Mulvihill, K. van Pee, &.#.2.1.4.;. Yildiz, W. Kühlbrandt, D.J. Müller, and G. Hummer. (2019). Membrane perforation by the pore-forming toxin pneumolysin. Proc. Natl. Acad. Sci. USA. [Epub: Ahead of Print]

Walev, I., S.C. Bhakdi, F. Hofmann, N. Djonder, A. Valeva, K. Aktories, and S. Bhakdi. (2001). Delivery of proteins into living cells by reversible membrane permeabilization with streptolysin-O. Proc. Natl. Acad. Sci. USA 98: 3185-3190.

Zafar, M.A., Y. Wang, S. Hamaguchi, and J.N. Weiser. (2017). Host-to-Host Transmission of Streptococcus pneumoniae Is Driven by Its Inflammatory Toxin, Pneumolysin. Cell Host Microbe 21: 73-83.

Examples:

TC#NameOrganismal TypeExample
1.C.12.1.1

Perfringolysin O, PFO.  Phosphatidylcholine in the outer leaflet increases the cholesterol concentration required to induce PFO binding while phosphatidylethanolamine and phosphatidylserine in the inner leaflet of asymmetric vesicles stabilized the formation of a deeply inserted conformation that does not form pores, even though it contains transmembrane segments (Lin and London 2014). This conformation may represent an important intermediate stage in PFO pore formation.  Cholesterol recognition, oligomerization, and the conformational changes involved in pore formation have been reviewed (Johnson and Heuck 2014), and the involvement of the D1 domain in structural transitions leading to pore formation has been studied (Kacprzyk-Stokowiec et al. 2014). Interaction of PFO with cholesterol is sufficient to initiate an irreversible sequence of coupled conformational changes that extend throughout the toxin molecule and induce pore formation (Heuck et al. 2007).  Once this transmembrane beta-barrel protein is inserted, PFO assembles into pore-forming oligomers containing 30-50 PFO monomers. These form a pore of up to 300 Å, far exceeding the size of most other proteinaceous pores.  Decreasing the length of the β-strands causes the pore to shrink (Lin et al. 2015). Site-directed mutagenesis data combined with binding studies performed with different sterols, and molecular modeling are beginning to shed light on the interaction with cholesterol (Savinov and Heuck 2017). Fine-tuning of the stability of beta-strands by Y181 in perfringolysin O directs the prepore to pore transition (Kulma et al. 2019).

	

Firmicutes

Perfringolysin O of Clostridium perfringens (P0C2E9)

 
1.C.12.1.10

CDC family protein of 588 aas

CDC protein of Treponema medium

 
1.C.12.1.11

CDC homologue of 511 aas

CDC protein of Deinococcus deserti

 
1.C.12.1.12

Uncharacterized protein of 656 aas

UP of Streptomyces mobaraensis

 
1.C.12.1.13

Intermedilysin of 532 aas and 1 N-terminal TMS.  It binds to membranes containing the human protein CD59 but forms pores only if the membrane contains sufficient cholesterol (Heuck et al. 2007).  CD59 is required for the specific coordination of intermedilysin (ILY) monomers and for triggering collapse of an oligomeric prepore. Movement of Domain 2 with respect to Domain 3 of ILY is essential for forming a late prepore intermediate that releases CD59, while the role of cholesterol may be limited to insertion of the TMSs (Boyd et al. 2016). The pore-forming regions are initially folded up on the surfaces of the soluble precursors. To create the transmembrane pores, these regions must extend and refold into membrane-inserted beta-barrels (Tilley and Saibil 2006).

Intermedilysin of Streptococcus intermedius

 
1.C.12.1.2Alveolysin Gram-positive bacteria Alveolysin of Bacillus alvei (P23564)
 
1.C.12.1.3

Cereolysin O (hemolysin I) (Ramarao and Sanchis 2013).

Gram-positive bacteria

Hemolysin I of Bacillus cereus (Q93LA9)

 
1.C.12.1.4

Streptolysin O (transports NAD-glycohydrolase into the host cell) (Meehl and Caparon, 2004).  Injections into cells modulates cell metabolism which induces streptolysin synthesis and S. pyogenes growth (Baruch et al. 2014).

Gram-positive bacteria

Streptolysin O of Streptococcus pyogenes (P0C0I3)

 
1.C.12.1.5

Pneumolysin (PLS) or Intermedilysin (ILY), the shortest members of the CDC family (Gonzalez et al., 2008). Exhibits a broad range of conductances (El-Rachkidy et al., 2008) and localizes to the cell wall of S. pneumoniae (Price and Camilli, 2009). Binding of ILY to human CD59 initiates a series of conformational changes within the toxin that result in the conversion of the soluble monomer into an oligomeric membrane-embedded pore complex. The assembly intermediates increase the sensitivity of the host cell to lysis by its complement membrane attack complex, apparently by blocking the hCD59-binding site for complement proteins C8α and C9 (LaChapelle et al., 2009).  The herbal bioflavonoid, Apigenin, inhibits oligomerization of PLY and protects against pneumonia (Song et al. 2016).  Pneumolysin alters lysosomal integrity in epithelial cells, but not in macrophages, inducing lysosomal membrane permeabilization and release of lysosomal content (Malet et al. 2016). A four-step mechanism of membrane attachment and pore formation has been proosed (van Pee et al. 2016). Pneumolysin is both necessary and sufficient to promote inflammation, increasing shedding and causing transmission to others (Zafar et al. 2017). The release of pneumococcal autolysin, which promotes cell lysis and the release of pneumolysin, is inhibited by treatment with azithromycin and erythromycin, but recombinant autolysin restores the release of pneumolysin (Domon et al. 2018). Pneumolyin exhibits direct cardiotoxic and immunosuppressive activities, as well as indirect pro-inflammatory/pro-thrombotic activities (Anderson et al. 2018). The transmembrane beta-hairpins of the PLY pore are stable only for oligomers, forming a curtain-like membrane-spanning beta-sheet, and its hydrophilic inner face draws water into the protein-lipid interface, forcing lipids to recede (Vögele et al. 2019).

Gram-positive bacteria

Pneumolysin of Streptococcus pneumoniae (P0C2J9)

 
1.C.12.1.6Ivanolysin Gram-positive bacteria Ivanolysin of Listeria ivanovii (P31831)
 
1.C.12.1.7

Listeriolysin O, Listeriolysin-O, LLO, Hly, HlyA, Lis of 507 aas and 1 N-terminal TMS (Viala et al., 2008). CFTR transiently increases phagosomal chloride concentrations after infection, potentiating pore formation and vacuole lysis. Thus, Listeria exploits mechanisms of cellular ion homeostasis to escape the phagosome (Radtke et al., 2011).  LLO is an example of a large beta-barrel pore that exhibits plasticity, controlled by environmental cues like pH (Podobnik et al. 2015).  Pore formation is a multistep process involving the sequential formation of arcs, slits, small rings and larger rings before formation of transmembrane pores (Mulvihill et al. 2015).  LLO promotes nanoscale membrane reorganization (Sarangi et al. 2016). It alters lysosomal integrity in epithelial cells, but not in macrophages, inducing lysosomal membrane permeabilization and release of lysosomal content (Malet et al. 2016). LLO pore activity is active at acidic pH (<6), but not at neutral pH because pore-formation is controlled by rapid, irreversible denaturation of its structure at neutral pH at temperatures >30 degrees C. Denaturation is triggered at neutral pH by the premature unfolding of the domain 3 transmembrane beta-hairpins, structures that normally form the transmembrane beta-barrel. A triad of acidic residues within domain 3 functions as the pH sensor (Schuerch et al. 2005).

Firmicutes

Listeriolysin O of Listeria monocytogenes (P13128)

 
1.C.12.1.8

Suilysin (SLY, a hemolysin) of 497 aas is a pore-forming cholesterol-dependent cytolysin of S. suis and a true virulence factor (Tenenbaum et al. 2016). It plays a role during the development of S. suis meningitis in pigs and humans, and is a potential vaccine candidate.

Gram-positive bacteria

Hemolysin of Streptococcus suis (O85102)

 
1.C.12.1.9

The cholesterol-dependent pore-forming cytoslysin, Pyolysin of 534 aas with one N-terminal TMS.  The pathology of Trueperella pyogenes and this pyolysin have been described and reviewed (Rzewuska et al. 2019).

Gram-positive bacteria

Pyolysin of Arcanobacterium pyogenes (Trueperella pyogenes) (O31241)

 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
1.C.12.2.1FlavomodulinBacteriaFlavomodulin of Flavobacterium psychrophilum (A6GVU3)
 
1.C.12.2.2

Uncharacterized protein of 373 aas

UP of Prevotella micans

 
1.C.12.2.3

Tetanolysin O of 369 aas.  A three dimensional model of the toxin is availalbe (Skariyachan et al. 2012).

Tetanolysin O of Capnocytophaga canimorsus

 
1.C.12.2.4

CDC homologue of 489 aas

CDC homologue of Chryseobacterium indologenes

 
Examples:

TC#NameOrganismal TypeExample
1.C.12.3.1Hypothetical Protein, HPBacteriaHP of Nostoc sp. PCC7120 (Q8YX86)
 
1.C.12.3.2

Cytolysin, a secreted calcineurin-like phosphatase of 361 aas

Cytolysin of Mesorhizobium loti

 
1.C.12.3.3

Cytolysin, a secreted calcineurin-like phosphatase of458 aas

Cytolysin of Candidatus Liberibacter americanus

 
Examples:

TC#NameOrganismal TypeExample