The thiol-activated Cholesterol-dependent Cytolysin (CDC) family
TC# 1.C.12
is a member of the MACPF superfamily. Cholesterol dependent cytolysins are a family of β-barrel pore-forming exotoxins that are secreted by

gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

bacteria. CDCs are secreted as water-soluble

monomer In chemistry, a monomer ( ; '' mono-'', "one" + ''-mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification ...

s of 50-70 kDa, that when bound to the target cell, form a circular homo-oligomeric complex containing as many as 40 (or more) monomers. Through multiple conformational changes, the β-barrel transmembrane structure (~250 Å in diameter depending on the toxin) is formed and inserted into the target cell membrane. The presence of

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

in the target membrane is required for pore formation, though the presence of cholesterol is not required by all CDCs for binding. For example, intermedilysin (ILY
TC# 1.C.12.1.5
secreted by '' Streptococcus intermedius'' will bind only to target membranes containing a specific protein receptor, independent of the presence of cholesterol, but cholesterol is required by intermedilysin (ILY
TC# 1.C.12.1.5
for pore formation. While the lipid environment of cholesterol in the membrane can affect toxin binding, the exact molecular mechanism that cholesterol regulates the cytolytic activity of the CDC is not fully understood.

Cyto-lethal effects

Once the pore is formed within the target cell membrane, the regulation of the

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

environment and what enters and leaves the cell is lost. The pore being ~250 Å in diameter is large enough to allow the loss of amino acids,

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules with ...

, small and large proteins, as well as ions (Ca²⁺,Na⁺, K⁺, etc.). The loss of calcium in particular, which is involved in multiple molecular pathways, will have a large impact on cell survival. The pore will also lead to an influx of water, which may lead to

blebbing In cell biology, a bleb is a bulge of the plasma membrane of a cell, characterized by a spherical, bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the internal structure of the cell, ...

and cell death.

Purpose

Bacteria invest energy into creating these toxins because they act as

virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

s. By targeting immune cells such as macrophages the bacteria will be protected against

phagocytosis Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...

and destruction by

respiratory burst Respiratory burst (or oxidative burst) is the rapid release of the reactive oxygen species (ROS), superoxide anion () and hydrogen peroxide (), from different cell types. This is usually utilised for mammalian immunological defence, but also play ...

Structure

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. CDCs with longer sequences usually display variations in the N-terminus, the functions of which are unknown for many members but for some are believed to serve various functions unrelated to secretion. For instance, listeriolysin O (LLO
TC# 1.C.12.1.7
from ''

Listeria monocytogenes ''Listeria monocytogenes'' is the species of pathogenic bacteria that causes the infection listeriosis. It is a facultative anaerobic bacterium, capable of surviving in the presence or absence of oxygen. It can grow and reproduce inside the host ...

'' exhibits a proline rich sequence at its

amino terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

that plays a role in the stability of LLO. The extreme case is lectinolysin (LLY
UniProt: B3UZR3
from some strains of ''Streptococcus mitis'' and ''S. pseudopneumoniae'' contain a functional fucose-binding lectin at the amino terminus. Furthermore, all CDCs contain a highly conserved undecapeptide, which is thought to be critical for cholesterol-mediated membrane recognition. The CDC monomer consist of 4 structural domains, with domain 4 (D4) being involved with membrane binding. Multiple CDC monomers will oligomerize once bound to the target cell membrane forming a β-barrel structure which will be inserted into the target cell membrane. The core section of amino acids, which are required for pore formation, are more conserved between CDCs, which is illustrated by similar three-dimensional structures and pore-forming mechanisms. The structurally conserved domain 4 of CDC contains four conserve loops L1-L3 and an undecapeptide region, which is believed to be involved in cholesterol dependent recognition. Single amino acid modifications in these loops prevented perfingolysin O (PFO
TC# 1.C.12.1.1
, which is a CDC secreted by ''

Clostridium perfringens ''Clostridium perfringens'' (formerly known as ''C. welchii'', or ''Bacillus welchii'') is a Gram-positive, rod-shaped, anaerobic, spore-forming pathogenic bacterium of the genus ''Clostridium''. ''C. perfringens'' is ever-present in nature an ...

'' from binding to cholesterol rich

liposome A liposome is a small artificial Vesicle (biology and chemistry), vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, lipo ...

s. More recently, Farrand et al. has shown that two amino acids, a threonine-leucine pair in loop L1, comprise the cholesterol binding motif and is conserved in all known CDCs. Some CDC protein crystal structures available in RCSB include: Undecapeptide

Prepore and pore assembly

The mechanism of pore formation of perfingolysin O (PFO
TC# 1.C.12.1.1
, which is secreted by ''

'', begins with encountering and binding to cholesterol on the target membrane. The C-terminus of PFO domain 4 (D4) encounters the membrane first. The binding of D4 triggers a structural rearrangement in which the PFO monomers oligomerize forming the pre-pore complex. PFO pre pore and pore

The binding of CDC to the target membrane is required for oligmerization. The oligomerization of the CDC requires the conversion of alpha-helical regions to amphipathic beta-strands that is initiated by protein-lipid interactions or protein-protein interactions. The water-soluble form of the toxins is prevented from oligomerizing by having the access of one edge of a core β-sheet in the monomer blocked. To be specific, β5, a short polypeptide loop, hydrogen-bonds to β4, preventing β4 interaction with β1 on the adjacent monomer. The binding of D4 to the membrane surface triggers a conformational change in domain 3, which rotates β5 away from β4, exposing β4 allowing it to interact with the β1 strand of another PFO molecule, initiating oligomerization. THM and beta subunits of PFO D4

Unlike most of the exposed surface residues of CDC that are not conserved the residues at the surface of the D4 tip, which are involved in membrane interactions, are highly conserved. Pore formation begins once two amphipathic transmembrane β-hairpins from ~35 PFO monomers are inserted in a concerted fashion, which then create a large β-barrel that perforates the membrane. The toxin gets around the

energy barrier In chemistry and physics, activation energy is the minimum amount of energy that must be provided for compounds to result in a chemical reaction. The activation energy (''E''a) of a reaction is measured in joules per mole (J/mol), kilojoules pe ...

, of inserting the CDC into the membrane, by the formation of the β-barrel, which will lower the energy requirements compared to what would be required for the insertion of single β-hairpins. In the water-soluble monomeric form of CDC, the transmembrane β-hairpins that are located on both sides of the central β-sheet on domain 3 are each folded as three short

α-helices The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues ear ...

to minimize the exposure of

hydrophobic residues Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

. The α-helices are inserted into the target cell membrane bilayer and a conformational change takes place into

amphipathic An amphiphile (from the Greek αμφις amphis, both, and φιλíα philia, love, friendship), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'') properties. Such a compoun ...

β-hairpins. A concerted mechanism of insertion is required so that the

hydrophilic A hydrophile is a molecule or other molecular entity that is attracted to water molecules and tends to be dissolved by water.Liddell, H.G. & Scott, R. (1940). ''A Greek-English Lexicon'' Oxford: Clarendon Press. In contrast, hydrophobes are ...

surfaces of the β-hairpins remain exposed to the aqueous medium, and not the hydrophobic membrane core. RIbbon structure of PFO

Six short α-helices in D3 unfold to form two transmembrane β-hairpin (TMH), TMH1 (red) and TMH2 (green). TMH formation in PFO

Specificity

The binding of CDC to its target membrane requires the recognition of

or in the case of intermedilysin (ILY
TC# 1.C.12.1.5
, the recognition of human CD59 membrane-anchored protein. The recognition of cholesterol provides specificity for eukaryotic cells and the specificity for the glycosylphosphatidylinositol-anchored protein CD59 provides specificity for human cells. Cholesterol is not required for intermedilysin (ILY) to bind to a target cell, as it uses human CD59 for initial attachment, but the presence of cholesterol is required for pore formation by all CDC. CDC are sensitive to both oxygen and cholesterol. Toxins isolated from culture

supernatant In an aqueous solution, precipitation is the process of transforming a dissolved substance into an insoluble solid from a super-saturated solution. The solid formed is called the precipitate. In case of an inorganic chemical reaction leading ...

s, pre-incubated with cholesterol, were inactivated once exposed to oxygen. CDC are also pH-sensitive. A change of pH in a medium from 7.4 to 6.0 caused a conformational change in perfringolysin O, leading to an alteration in the minimum cholesterol threshold required for binding. Another CDC, listeriolysin O (LLO), which functions at an acidic pH, will lose its function at a neutral pH at temperatures above 30 °C, which trigger the irreversible loss of activity by the unfolding of domain 3 in the soluble monomer.

Role of cholesterol

The presence of cholesterol in the membrane of the target cell is required for CDC pore formation. The arrangement of cholesterol molecules in the bilayer may also be important for successful binding. The non-polar hydrocarbon tail of cholesterol orients itself toward the hydrophobic center of the membrane lipid bilayer, while the 3-β-OH group is oriented closer to the ester bonds formed by the fatty acid chains, and glycerol backbones closer to the membrane surface. Even with the 3-β-OH group near the membrane surface, it is not very exposed compared to the phospholipid head groups. The availability of cholesterol at the membrane surface is dependent upon its interaction with other membrane components such as phospholipids and proteins; and the more cholesterol interacts with these components the less available it is to interact with extramembranous molecules. Some factors that affect cholesterols availability are size of the polar head groups and the ability of the phospholipid to hydrogen bond with the 3-β-OH group of cholesterol. Cholesterol associates with phospholipids, forming a stoichiometric complex and contributes to membrane fluidity. If cholesterol concentration exceeds a certain point, free cholesterol will begin to precipitate out of the membrane. The binding and pore formation of CDC will occur when the concentration of cholesterol exceeds the association capacity of the phospholipids, allowing the excess cholesterol to associate with the toxin. The presence of cholesterol aggregates in an aqueous solution were sufficient to initiate a conformation change and oligomerization of perfringolysin O (PFO), while no changes were seen by perfingolysin O with epicholesterol aggregates in solution. Epicholesterol is a sterol that differs from cholesterol by the orientation of the 3-β-OH group, which is axial in epicholesterol and equatorial in cholesterol. Since the orientation of the hydroxyl group has such an effect on the bind/pore-formation of CDC, the equatorial conformation may be required for docking of the sterol to the binding pocket in domain 4, or to be properly exposed at the surface of lipid structures.

The conserved undecapeptide (Tryptophan-rich motif) of the CDCs

The conserved undecapeptide motif (ECTGLAWEWWR) in domain 4 of the CDCs is the signature motif of the CDCs and was originally thought to be the cholesterol binding motif, but that was shown to be incorrect in a number of studies and now, as described above, Farrand et al. showed that the cholesterol binding motif is a threonine-leucine pair in loop 1 at the base of domain 4. It has since been shown that the conserved

undecapeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

is a key element in the allosteric pathway that couples membrane binding to the initiation of structural changes in domain 3 of the CDC monomer that allows it to begin the process of oligomerization into the prepore complex.

Effects of other membrane lipids

The phospholipid composition of a cell membrane affects the arrangement of cholesterol within the membrane and the ability for CDC to bind and initiate pore-formation. For example, perfringolysin O will preferentially bind to cholesterol-rich membranes composed mainly of phospholipids containing 18-carbon acyl chains. Lipids having a conical molecular shape alter the energetic state of membrane cholesterol, augmenting the interaction of the sterol with the cholesterol-specific

cytolysin Cytolysin refers to the substance secreted by microorganisms, plants or animals that is specifically toxic to individual cells, in many cases causing their dissolution through lysis. Cytolysins that have a specific action for certain cells are n ...

. Since high cholesterol concentrations are required for CDC binding/pore-formation, it was thought that CDC would associate with

lipid raft The plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein receptors organised in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular membranes remains somewhat controversial ...

s. A later study showed that

sphingomyelin Sphingomyelin (SPH, ˌsfɪŋɡoˈmaɪəlɪn) is a type of sphingolipid found in animal cell membranes, especially in the membranous myelin sheath that surrounds some nerve cell axons. It usually consists of phosphocholine and ceramide, or a phosp ...

, a necessary component of lipid raft formation, inhibited rather than promoted the binding of perfringolysin O to the target membrane.

Possible coordination with other toxins

It is possible that the exposure of cholesterol at the membrane surface might be facilitated by other membrane-damaging toxins secreted such as phospholipase C, which cleave the head groups of phospholipids increasing the exposure of cholesterol. Two organisms, ''Clostridium perfringens'' that produces perfringolysin O (CDC) and α-toxin during '' clostridial myonecrosis'' and ''

'' which releases

listeriolysin O Listeriolysin O (LLO) is a hemolysin produced by the bacterium ''Listeria monocytogenes'', the pathogen responsible for causing listeriosis. The toxin may be considered a virulence factor, since it is crucial for the virulence of ''L. monocytogenes ...

(CDC) and phospholipases C leading to the virulence of these bacteria. However, although the ''C. perfringens'' α-toxin treatment of liposome membranes increase the activity of PFO on those membranes this affect does not appear to aways be the case "in vivo". During ''C. perfringens'' gas gangrene (myonecrosis) the main site of action of the ''C. perfringens'' α-toxin is the muscle tissue, where the cleavage of the phospholipid head groups does not seem to increase the activity of perfringolysin O on this tissue, as knockouts of PFO do not appear to significantly alter the course of the myonecrosis. Therefore, cleavage of the headgroups in the muscle tissue by α-toxin does not appear to result in a significant increase in PFO activity on this tissue.

Examples

* Intermedilysin O *Lectinolysin *

Listeriolysin O Listeriolysin O (LLO) is a hemolysin produced by the bacterium ''Listeria monocytogenes'', the pathogen responsible for causing listeriosis. The toxin may be considered a virulence factor, since it is crucial for the virulence of ''L. monocytogenes ...

* Perfringolysin O * Pneumolysin * Suilysin O *

Streptolysin Streptolysins are two hemolytic exotoxins from ''Streptococcus''. Types include streptolysin O (SLO; ''slo''), which is oxygen-labile, and streptolysin S (SLS; ''sagA''), which is oxygen-stable. SLO is part of the thiol-activated cytolysin fami ...

O * Tetanolysin

References

{{Reflist, 32em, refs= {{cite book , last = Alberts , first = Bruce , name-list-style = vanc , title = Molecular Biology of the Cell , edition = 5th , location = New York , publisher = Garland Science , date = 2008 {{cite journal , vauthors = Alberti-Segui C, Goeden KR, Higgins DE , title = Differential function of Listeria monocytogenes listeriolysin O and phospholipases C in vacuolar dissolution following cell-to-cell spread , journal = Cellular Microbiology , volume = 9 , issue = 1 , pages = 179–95 , date = January 2007 , pmid = 17222191 , doi = 10.1111/j.1462-5822.2006.00780.x , doi-access = free Alouf, J. E., Billington, S. J. & Jost, B. H. (2006) Repertoire and general features of the family of cholesterol-dependent cytolysins. In Alouf, J. E. & Popoff, M. R. (Eds.) The Comprehensive Sourcebook of Bacterial Protein Toxins. 3rd ed., pp. 643-658, Oxford, England. Academic Press {{cite journal , vauthors = Awad MM, Ellemor DM, Boyd RL, Emmins JJ, Rood JI , title = Synergistic effects of alpha-toxin and perfringolysin O in Clostridium perfringens-mediated gas gangrene , journal = Infection and Immunity , volume = 69 , issue = 12 , pages = 7904–10 , date = December 2001 , pmid = 11705975 , pmc = 98889 , doi = 10.1128/IAI.69.12.7904-7910.2001 {{cite journal , vauthors = Czajkowsky DM, Hotze EM, Shao Z, Tweten RK , title = Vertical collapse of a cytolysin prepore moves its transmembrane beta-hairpins to the membrane , journal = The EMBO Journal , volume = 23 , issue = 16 , pages = 3206–15 , date = August 2004 , pmid = 15297878 , doi = 10.1038/sj.emboj.7600350 , pmc = 514522 {{cite journal , vauthors = Dang TX, Hotze EM, Rouiller I, Tweten RK, Wilson-Kubalek EM , title = Prepore to pore transition of a cholesterol-dependent cytolysin visualized by electron microscopy , journal = Journal of Structural Biology , volume = 150 , issue = 1 , pages = 100–8 , date = April 2005 , pmid = 15797734 , doi = 10.1016/j.jsb.2005.02.003 {{cite journal , vauthors = Dowd KJ, Farrand AJ, Tweten RK , title = The cholesterol-dependent cytolysin signature motif: a critical element in the allosteric pathway that couples membrane binding to pore assembly , journal = PLOS Pathogens , volume = 8 , issue = 7 , pages = e1002787 , year = 2012 , pmid = 22792065 , doi = 10.1371/journal.ppat.1002787 , pmc = 3390400 {{cite journal , vauthors = Farrand S, Hotze E, Friese P, Hollingshead SK, Smith DF, Cummings RD, Dale GL, Tweten RK , title = Characterization of a streptococcal cholesterol-dependent cytolysin with a lewis y and b specific lectin domain , journal = Biochemistry , volume = 47 , issue = 27 , pages = 7097–107 , date = July 2008 , pmid = 18553932 , pmc = 2622431 , doi = 10.1021/bi8005835 {{cite journal , vauthors = Feil SC, Lawrence S, Mulhern TD, Holien JK, Hotze EM, Farrand S, Tweten RK, Parker MW , title = Structure of the lectin regulatory domain of the cholesterol-dependent cytolysin lectinolysin reveals the basis for its lewis antigen specificity , journal = Structure , volume = 20 , issue = 2 , pages = 248–58 , date = February 2012 , pmid = 22325774 , pmc = 3682648 , doi = 10.1016/j.str.2011.11.017 {{cite journal , vauthors = Farrand AJ, LaChapelle S, Hotze EM, Johnson AE, Tweten RK , title = Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 107 , issue = 9 , pages = 4341–6 , date = March 2010 , pmid = 20145114 , pmc = 2840085 , doi = 10.1073/pnas.0911581107 , bibcode = 2010PNAS..107.4341F , doi-access = free {{cite journal , vauthors = Flanagan JJ, Tweten RK, Johnson AE, Heuck AP , title = Cholesterol exposure at the membrane surface is necessary and sufficient to trigger perfringolysin O binding , journal = Biochemistry , volume = 48 , issue = 18 , pages = 3977–87 , date = May 2009 , pmid = 19292457 , pmc = 2825173 , doi = 10.1021/bi9002309 {{cite journal , vauthors = Giddings KS, Johnson AE, Tweten RK , title = Redefining cholesterol's role in the mechanism of the cholesterol-dependent cytolysins , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 100 , issue = 20 , pages = 11315–20 , date = September 2003 , pmid = 14500900 , pmc = 208754 , doi = 10.1073/pnas.2033520100 , bibcode = 2003PNAS..10011315G , doi-access = free {{cite book , vauthors = Heuck AP, Moe PC, Johnson BB , title = Cholesterol Binding and Cholesterol Transport Proteins , chapter = The cholesterol-dependent cytolysin family of gram-positive bacterial toxins , volume = 51 , pages = 551–77 , year = 2010 , pmid = 20213558 , doi = 10.1007/978-90-481-8622-8_20 , series = Subcellular Biochemistry , isbn = 978-90-481-8621-1 {{cite journal , vauthors = Heuck AP, Savva CG, Holzenburg A, Johnson AE , title = Conformational changes that effect oligomerization and initiate pore formation are triggered throughout perfringolysin O upon binding to cholesterol , journal = The Journal of Biological Chemistry , volume = 282 , issue = 31 , pages = 22629–37 , date = August 2007 , pmid = 17553799 , doi = 10.1074/jbc.M703207200 , doi-access = free {{cite journal , vauthors = Hotze EM, Heuck AP, Czajkowsky DM, Shao Z, Johnson AE, Tweten RK , title = Monomer-monomer interactions drive the prepore to pore conversion of a beta-barrel-forming cholesterol-dependent cytolysin , journal = The Journal of Biological Chemistry , volume = 277 , issue = 13 , pages = 11597–605 , date = March 2002 , pmid = 11799121 , doi = 10.1074/jbc.m111039200 , doi-access = free {{cite journal , vauthors = Hotze EM, Wilson-Kubalek E, Farrand AJ, Bentsen L, Parker MW, Johnson AE, Tweten RK , title = Monomer-monomer interactions propagate structural transitions necessary for pore formation by the cholesterol-dependent cytolysins , journal = The Journal of Biological Chemistry , volume = 287 , issue = 29 , pages = 24534–43 , date = July 2012 , pmid = 22645132 , pmc = 3397878 , doi = 10.1074/jbc.m112.380139 , doi-access = free {{cite journal , vauthors = Hotze EM, Wilson-Kubalek EM, Rossjohn J, Parker MW, Johnson AE, Tweten RK , title = Arresting pore formation of a cholesterol-dependent cytolysin by disulfide trapping synchronizes the insertion of the transmembrane beta-sheet from a prepore intermediate , journal = The Journal of Biological Chemistry , volume = 276 , issue = 11 , pages = 8261–8 , date = March 2001 , pmid = 11102453 , doi = 10.1074/jbc.m009865200 , doi-access = free {{cite journal , vauthors = Nelson LD, Johnson AE, London E , title = How interaction of perfringolysin O with membranes is controlled by sterol structure, lipid structure, and physiological low pH: insights into the origin of perfringolysin O-lipid raft interaction , journal = The Journal of Biological Chemistry , volume = 283 , issue = 8 , pages = 4632–42 , date = February 2008 , pmid = 18089559 , doi = 10.1074/jbc.m709483200 , doi-access = free {{cite journal , vauthors = Ohno-Iwashita Y, Iwamoto M, Ando S, Iwashita S , title = Effect of lipidic factors on membrane cholesterol topology--mode of binding of theta-toxin to cholesterol in liposomes , journal = Biochimica et Biophysica Acta (BBA) - Biomembranes , volume = 1109 , issue = 1 , pages = 81–90 , date = August 1992 , pmid = 1504083 , doi = 10.1016/0005-2736(92)90190-W {{cite journal , vauthors = Ramachandran R, Heuck AP, Tweten RK, Johnson AE , title = Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin , journal = Nature Structural Biology , volume = 9 , issue = 11 , pages = 823–7 , date = November 2002 , pmid = 12368903 , doi = 10.1038/nsb855 , s2cid = 11966 {{cite journal , vauthors = Ramachandran R, Tweten RK, Johnson AE , title = Membrane-dependent conformational changes initiate cholesterol-dependent cytolysin oligomerization and intersubunit beta-strand alignment , journal = Nature Structural & Molecular Biology , volume = 11 , issue = 8 , pages = 697–705 , date = August 2004 , pmid = 15235590 , doi = 10.1038/nsmb793 , s2cid = 29393426 {{cite journal , vauthors = Rossjohn J, Feil SC, McKinstry WJ, Tweten RK, Parker MW , title = Structure of a cholesterol-binding, thiol-activated cytolysin and a model of its membrane form , journal = Cell , volume = 89 , issue = 5 , pages = 685–92 , date = May 1997 , pmid = 9182756 , doi = 10.1016/s0092-8674(00)80251-2 , doi-access = free {{cite journal , vauthors = Schnupf P, Portnoy DA, Decatur AL , title = Phosphorylation, ubiquitination and degradation of listeriolysin O in mammalian cells: role of the PEST-like sequence , journal = Cellular Microbiology , volume = 8 , issue = 2 , pages = 353–64 , date = February 2006 , pmid = 16441444 , doi = 10.1111/j.1462-5822.2005.00631.x , doi-access = free {{cite journal , vauthors = Schuerch DW, Wilson-Kubalek EM, Tweten RK , title = Molecular basis of listeriolysin O pH dependence , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 102 , issue = 35 , pages = 12537–42 , date = August 2005 , pmid = 16105950 , pmc = 1194900 , doi = 10.1073/pnas.0500558102 , bibcode = 2005PNAS..10212537S , doi-access = free {{cite journal , vauthors = Shatursky O, Heuck AP, Shepard LA, Rossjohn J, Parker MW, Johnson AE, Tweten RK , title = The mechanism of membrane insertion for a cholesterol-dependent cytolysin: a novel paradigm for pore-forming toxins , journal = Cell , volume = 99 , issue = 3 , pages = 293–9 , date = October 1999 , pmid = 10555145 , doi = 10.1016/s0092-8674(00)81660-8 , doi-access = free {{cite journal , vauthors = Shepard LA, Heuck AP, Hamman BD, Rossjohn J, Parker MW, Ryan KR, Johnson AE, Tweten RK , title = Identification of a membrane-spanning domain of the thiol-activated pore-forming toxin Clostridium perfringens perfringolysin O: an alpha-helical to beta-sheet transition identified by fluorescence spectroscopy , journal = Biochemistry , volume = 37 , issue = 41 , pages = 14563–74 , date = October 1998 , pmid = 9772185 , doi = 10.1021/bi981452f {{cite journal , vauthors = Shepard LA, Shatursky O, Johnson AE, Tweten RK , title = The mechanism of pore assembly for a cholesterol-dependent cytolysin: formation of a large prepore complex precedes the insertion of the transmembrane beta-hairpins , journal = Biochemistry , volume = 39 , issue = 33 , pages = 10284–93 , date = August 2000 , pmid = 10956018 , doi = 10.1021/bi000436r {{cite journal , vauthors = Soltani CE, Hotze EM, Johnson AE, Tweten RK , title = Structural elements of the cholesterol-dependent cytolysins that are responsible for their cholesterol-sensitive membrane interactions , journal = Proceedings of the National Academy of Sciences of the United States of America , volume = 104 , issue = 51 , pages = 20226–31 , date = December 2007 , pmid = 18077338 , pmc = 2154413 , doi = 10.1073/pnas.0708104105 , bibcode = 2007PNAS..10420226S , doi-access = free {{cite journal , vauthors = Tilley SJ, Orlova EV, Gilbert RJ, Andrew PW, Saibil HR , title = Structural basis of pore formation by the bacterial toxin pneumolysin , journal = Cell , volume = 121 , issue = 2 , pages = 247–56 , date = April 2005 , pmid = 15851031 , doi = 10.1016/j.cell.2005.02.033 , doi-access = free {{cite journal , vauthors = Zitzer A, Westover EJ, Covey DF, Palmer M , title = Differential interaction of the two cholesterol-dependent, membrane-damaging toxins, streptolysin O and Vibrio cholerae cytolysin, with enantiomeric cholesterol , journal = FEBS Letters , volume = 553 , issue = 3 , pages = 229–31 , date = October 2003 , pmid = 14572629 , doi = 10.1016/S0014-5793(03)01023-8 , doi-access = free

External links

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