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 In protein structures, a beta barrel (β barrel) is a beta sheet (β sheet) composed of Protein tandem repeats, tandem repeats that twists and coils to form a closed toroidal structure in which the first strand is bonded to the last strand (hydrog ...

exotoxin An exotoxin is a toxin secreted by bacteria. An exotoxin can cause damage to the host by destroying cells or disrupting normal cellular metabolism. They are highly potent and can cause major damage to the host. Exotoxins may be secreted, or, sim ...

s 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. The Gram stain is ...

bacteria. CDCs are secreted as water-soluble

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

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 the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

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 Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...

nucleotides Nucleotides are Organic compound, organic molecules composed of a nitrogenous base, a pentose sugar and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both o ...

, 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 (or snout) is a bulge of the plasma membrane of a cell, characterized by a spherical, "blister-like", bulky morphology. It is characterized by the decoupling of the cytoskeleton from the plasma membrane, degrading the inte ...

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 botany) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following: * c ...

s. By targeting immune cells such as

macrophage Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

s the bacteria will be protected against

phagocytosis Phagocytosis () is the process by which a cell (biology), 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 ph ...

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 pl ...

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 ho ...

'' exhibits a

proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the p ...

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

oligomer In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relativ ...

ize 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 perfringolysin 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, bacillus (rod-shaped), anaerobic, spore-forming pathogenic bacterium of the genus '' Clostridium''. ''C. perfringens'' is ever-present ...

'' from binding to cholesterol rich

liposome A liposome is a small artificial vesicle, spherical in shape, having at least one lipid bilayer. Due to their hydrophobicity and/or hydrophilicity, biocompatibility, particle size and many other properties, liposomes can be used as drug deliver ...

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 perfringolysin 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 The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...

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 oligomerization. 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 the Arrhenius model of reaction rates, activation energy is the minimum amount of energy that must be available to reactants for a chemical reaction to occur. The activation energy (''E''a) of a reaction is measured in kilojoules per mole (k ...

, 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 An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix). The alpha helix is the most common structural arrangement in the secondary structure of proteins. It is also the most extreme type of l ...

to minimize the exposure of hydrophobic residues. The α-helices are inserted into the target cell membrane bilayer and a conformational change takes place into

amphipathic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

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 n ...

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 "sedimentation of a solid material (a precipitate) from a liquid solution". The solid formed is called the precipitate. In case of an inorganic chemical reaction leading to precipitation, the chemic ...

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 Phospholipids are a class of lipids whose molecule has a hydrophilic "head" containing a phosphate group and two hydrophobic "tails" derived from fatty acids, joined by an alcohol residue (usually a glycerol molecule). Marine phospholipids typ ...

hydrogen bond In chemistry, a hydrogen bond (H-bond) is a specific type of molecular interaction that exhibits partial covalent character and cannot be described as a purely electrostatic force. It occurs when a hydrogen (H) atom, Covalent bond, covalently b ...

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 perfringolysin O with epicholesterol aggregates in solution. Epicholesterol is a

sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...

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 In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

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 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 ...

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

lipid raft The cell membrane, plasma membranes of cells contain combinations of glycosphingolipids, cholesterol and protein Receptor (biochemistry), receptors organized in glycolipoprotein lipid microdomains termed lipid rafts. Their existence in cellular me ...

s. A later study showed that

sphingomyelin Sphingomyelin (SPH, ) 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 phosphoethanolamine hea ...

, 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 Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...

, 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 (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 * Perfringolysin O * Pneumolysin * Suilysin O *

Streptolysin Streptolysins are two homogenous exotoxins from ''Streptococcus pyogenes''. 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 c ...

O *

Tetanolysin Tetanolysin is a toxin produced by '' Clostridium tetani'' bacteria. Its function is unknown, but it is believed to contribute to the pathogenesis of tetanus. The other ''C. tetani'' toxin, tetanospasmin, is more definitively linked to tetanus. It ...

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External links

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