Redefining cholesterol's role in the mechanism of the cholesterol-dependent cytolysins

Giddings, Kara S.; Johnson, Arthur E.; Tweten, Rodney K.

doi:10.1073/pnas.2033520100

Cited by 175 publications

(205 citation statements)

References 41 publications

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“…Although inhibition of toxin A-induced 86 Rb ϩ efflux was complete after cholesterol depletion by methyl-␤-cyclodextrin, it is difficult to discriminate between a "specific" effect of cholesterol in membrane insertion from a modifying effect of cholesterol depending on increase in membrane fluidity and/or lateral segregation of lipids and formation of microdomains. Besides maintaining the membrane fluidity, cholesterol facilitates the conversion of lamellar lipid structure to inverted hexagonal structures (61), which may have a facilitating role in insertion of transmembrane peptide structures (62). Whether cholesterol directly influences C. difficile toxin activity, e.g.…”

Section: Discussionmentioning

confidence: 99%

Alternative Splicing in Class V Myosins Determines Association with Rab10

Roland

Lapierre

Goldenring

2009

Journal of Biological Chemistry

102

142

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Section: Discussionmentioning

confidence: 99%

Alternative Splicing in Class V Myosins Determines Association with Rab10

Roland

Lapierre

Goldenring

2009

Journal of Biological Chemistry

102

142

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“…Thereby, SipB and IpaB might form pores similar to cholesterol-dependent cytolysins. It remains to be determined whether cholesterol only acts as a translocator receptor or is also involved in circular oligomerization of monomers and penetration of the pre-pore into the membrane, as has been found for cholesterol-dependent cytolysins (Giddings et al, 2003).…”

Section: Type III Secretion Systemmentioning

confidence: 97%

“…However, cholesterol was found to play a more important role in insertion of the pre-pore β-barrel than in being a receptor for CDCs. Indeed, depletion of membrane cholesterol prevents pore formation by streptolysin O and intermedilysin, other CDC members from S. pyogenes and Streptococcus intermedius respectively, but does not greatly impair the binding of PFO (Giddings et al, 2003). CDCs exhibit a novel mode of action in which the toxin receptor has multiple roles in binding, pore formation and stabilization.…”

Section: Lipids and Pfts (Pore-forming Toxins)mentioning

confidence: 99%

Bacterial protein toxins and lipids: pore formation or toxin entry into cells

Geny

Popoff

2006

Biology of the Cell

118

104

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Lipids are hydrophobic molecules which play critical functions in cells, in particular, they are essential constituents of membranes, whereas bacterial toxins are mainly hydrophilic proteins. All bacterial toxins interact first with their target cells by recognizing a surface receptor, which is either a lipid or a lipid derivative, or another compound but in a lipid environment. Most bacterial toxins are PFTs (pore‐forming toxins) which oligomerize and insert into the lipid bilayer. A common mechanism of action involves the formation of a β‐barrel structure, resulting from the assembly of individual β‐hairpin(s) from individual monomers. An essential step for intracellular active toxins is to translocate their enzymatic part into the cytosol. Some toxins use a translocation mechanism based on pore formation similar to that of PFTs, others undergo a yet unclear ‘chaperone’ process.

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“…ILY was active only on human cells (20), a feature seemingly inconsistent with the "cholesterol as receptor" paradigm. Giddings et al subsequently showed that ILY used human CD59 (hCD59) as its membrane receptor (21), but pore formation by ILY still required cholesterol (22). This enigma was partially resolved by Soltani et al (23), who showed that ILY loops L1-L3 underwent a cholesterol-dependent membrane insertion after ILY bound to hCD59.…”

mentioning

confidence: 99%

Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface

Farrand

LaChapelle

Hotze

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The recognition and binding of cholesterol is an important feature of many eukaryotic, viral, and prokaryotic proteins, but the molecular details of such interactions are understood only for a few proteins. The pore-forming cholesterol-dependent cytolysins (CDCs) contribute to the pathogenic mechanisms of a large number of Grampositive bacteria. Cholesterol dependence of the CDC mechanism is a hallmark of these toxins, yet the identity of the CDC cholesterol recognition motif has remained elusive. 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 constitutes a common structural basis for mediating CDC-cholesterol recognition and binding, and defines a unique paradigm for membrane cholesterol recognition by surface-binding proteins.M embrane cholesterol is important to a variety of pathogenic processes that include virus fusion and budding (1) and the mechanisms of eukaryotic (2, 3) and prokaryotic toxins (4-7). Whether cholesterol is bound directly by these proteins as a receptor or it indirectly influences the binding or activity of the protein at the membrane surface remains unknown. The cholesterol-dependent cytolysins (CDCs) use cholesterol as their receptor at the membrane surface (7) and contribute to the pathogenesis of a large number of Gram-positive bacterial pathogens (8). The CDC-sterol interaction initiates a cascade of secondary and tertiary structural changes that lead to the formation of a large oligomeric complex, and ultimately a pore in the membrane of eukaryotic cells (9-13). Although significant progress has been made in understanding the assembly of the CDC pore complex, the structural basis for recognition and binding to cholesterol-rich membranes remains elusive.Early studies with the Clostridium perfringens perfringolysin O (PFO) suggested that the highly conserved tryptophan-rich undecapeptide sequence at the base of domain 4 (14, 15) (Fig. S1) mediated the PFO-cholesterol interaction. However, recent studies by Soltani et al. (16) uncoupled cholesterol binding from the undecapeptide and showed that the membrane insertion of loops L1-L3 at the base of domain 4 was cholesterol dependent (Fig. S1). These observations are also consistent with a lack of conservation of the 3D structures of the undecapeptide in the closely related CDCs PFO (17) and Bacillus anthracis anthrolysin O (ALO) (18) (Fig. S1). These studies suggest the residues that comprise the cholesterol recognition motif are located within L1-L3 because these loops and the undecapeptide are the only structures at the tip of domain 4 exposed to the nonpolar bilayer core; the rest of the domain 4 surface is surrounded by water (19).Cholesterol was thought to function as the sole CDC receptor until the discovery of intermedilysin (ILY), a CDC fr...

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Redefining cholesterol's role in the mechanism of the cholesterol-dependent cytolysins

Cited by 175 publications

References 41 publications

Alternative Splicing in Class V Myosins Determines Association with Rab10

Alternative Splicing in Class V Myosins Determines Association with Rab10

Bacterial protein toxins and lipids: pore formation or toxin entry into cells

Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface

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