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Review
. 2005 Oct;73(10):6199-209.
doi: 10.1128/IAI.73.10.6199-6209.2005.

Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins

Rodney K Tweten  1
Affiliations
Review

Cholesterol-dependent cytolysins, a family of versatile pore-forming toxins

Rodney K Tweten. Infect Immun. 2005 Oct.
No abstract available

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Figures

FIG. 1.
FIG. 1.
Crystal structures of PFO and ILY. Shown are the ribbon representations of the α-carbon backbone structures of PFO and ILY (72, 80). The locations of TMH1 and TMH2 (magenta), the three domain 4 loops of Ramachandran et al. (Loops 1 through 3) (yellow), the undecapeptide (red), residues Y181 and F318 (green), the β5-α1 loop (light blue), and β-strands β1 and β4 of the domain 3 core β-sheet are shown for PFO. Most of the corresponding regions are shown for ILY on the right and are color coded as for PFO. D1 through D4, domains 1 through 4, respectively.
FIG. 2.
FIG. 2.
The CDC pore-forming mechanism. The first step in the CDC mechanism is the interaction of the soluble CDC monomers with the host membrane. Binding to cholesterol-rich membranes, presumably via lipid rafts, appears to be mediated by the undecapeptide of many CDCs; however, the CDC from Streptococcus intermedius, ILY, has been shown to have a modified undecapeptide that has lost this function. Instead, ILY binds to human CD59 (R) and the CD59 binding site is contained elsewhere in the domain 4 structure. Upon membrane binding (either by direct binding to cholesterol-rich membranes or via a specific receptor), structural changes within domain 3 are triggered that initiate oligomerization of the membrane-bound monomers into the prepore structure (29, 33, 75-77, 89). The insertion of the undecapeptide tryptophans also appears to control the next stage of the CDC mechanism, prepore-to-pore conversion (19), in which the domain 3 α-helical bundles unravel to form TMH1 and TMH2 and each monomer of the prepore contributes these two β-hairpins to the ultimate formation of the transmembrane β-barrel. The formation of a preinsertion β-barrel is hypothesized, but as described in the text, its formation would be the most energetically favorable structure for the TMHs when they are inserted into the membrane to form the β-barrel pore. Cooperation of the monomers appears necessary for the membrane insertion of the TMHs (32). Upon conversion of the prepore to pore, the domain 2 structure appears to collapse, which brings domains 1 and 3 35 to 40 Å closer to the membrane and allows the transmembrane β-barrel to insert across the bilayer (12, 76, 87, 88). Depletion of membrane cholesterol blocks the prepore-to-pore transition.
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References

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