Pore formation: An ancient yet complex form of attack

Iacovache, Ioan; Goot, F. Gisou van der; Pernot, L.

doi:10.1016/j.bbamem.2008.01.026

Cited by 165 publications

(150 citation statements)

References 135 publications

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“…The majority of bacterial PFTs are ␤-PFTs, which also form the most-studied group (227). The large-pore-forming cholesterol-dependent cytolysins (CDCs), produced by Gram-positive and some Gram-negative bacteria, are a ␤-PFT subclass (4,227,228).…”

Section: Pft Mechanism Of Actionmentioning

confidence: 99%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

350

351

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SUMMARY Pore-forming toxins (PFTs) are the most common bacterial cytotoxic proteins and are required for virulence in a large number of important pathogens, including Streptococcus pneumoniae , group A and B streptococci, Staphylococcus aureus , Escherichia coli , and Mycobacterium tuberculosis . PFTs generally disrupt host cell membranes, but they can have additional effects independent of pore formation. Substantial effort has been devoted to understanding the molecular mechanisms underlying the functions of certain model PFTs. Likewise, specific host pathways mediating survival and immune responses in the face of toxin-mediated cellular damage have been delineated. However, less is known about the overall functions of PFTs during infection in vivo . This review focuses on common themes in the area of PFT biology, with an emphasis on studies addressing the roles of PFTs in in vivo and ex vivo models of colonization or infection. Common functions of PFTs include disruption of epithelial barrier function and evasion of host immune responses, which contribute to bacterial growth and spreading. The widespread nature of PFTs make this group of toxins an attractive target for the development of new virulence-targeted therapies that may have broad activity against human pathogens.

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Section: Pft Mechanism Of Actionmentioning

confidence: 99%

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Los

Randis

Aroian

et al. 2013

Microbiol Mol Biol Rev

350

351

View full text Add to dashboard Cite

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“…P athogenic bacteria secrete various virulence factors to attack host cells. The pore-forming toxins (PFTs) are among the most sophisticated virulence factors, and are expressed as watersoluble monomeric proteins that assemble on the membranes of the target cells to form bilayer-spanning pores (1). With the appearance of the pore on the membrane, the cells are killed through leakage.…”

mentioning

confidence: 99%

Crystal structure of the octameric pore of staphylococcal γ-hemolysin reveals the β-barrel pore formation mechanism by two components

Yamashita

Kawai

Tanaka

et al. 2011

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

154

210

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Staphylococcal γ-hemolysin is a bicomponent pore-forming toxin composed of LukF and Hlg2. These proteins are expressed as watersoluble monomers and then assemble into the oligomeric pore form on the target cell. Here, we report the crystal structure of the octameric pore form of γ-hemolysin at 2.5 Å resolution, which is the first high-resolution structure of a β-barrel transmembrane protein composed of two proteins reported to date. The octameric assembly consists of four molecules of LukF and Hlg2 located alternately in a circular pattern, which explains the biochemical data accumulated over the past two decades. The structure, in combination with the monomeric forms, demonstrates the elaborate molecular machinery involved in pore formation by two different molecules, in which interprotomer electrostatic interactions using loops connecting β2 and β3 (loop A: Asp43-Lys48 of LukF and Lys37-Lys43 of Hlg2) play pivotal roles as the structural determinants for assembly through unwinding of the N-terminal β-strands (aminolatch) of the adjacent protomer, releasing the transmembrane stem domain folded into a β-sheet in the monomer (prestem), and interaction with the adjacent protomer.

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“…Although VCC's involvement as a virulence factor in the human cholera pandemic remains unclear, this toxin belongs to a much larger class of pore-forming toxins (PFTs) secreted by a wide variety of human pathogens (5). PFTs are released by bacteria as water-soluble species and can attack cells at a distance, especially if they enter into the bloodstream.…”

mentioning

confidence: 99%

Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore-forming toxins

Olson²

2011

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

118

163

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Pore-forming toxins (PFTs) are potent cytolytic agents secreted by pathogenic bacteria that protect microbes against the cellmediated immune system (by targeting phagocytic cells), disrupt epithelial barriers, and liberate materials necessary to sustain growth and colonization. Produced by gram-positive and gramnegative bacteria alike, PFTs are released as water-soluble monomeric or dimeric species, bind specifically to target membranes, and assemble transmembrane channels leading to cell damage and/or lysis. Structural and biophysical analyses of individual steps in the assembly pathway are essential to fully understanding the dynamic process of channel formation. To work toward this goal, we solved by X-ray diffraction the 2.9-Å structure of the 450-kDa heptameric Vibrio cholerae cytolysin (VCC) toxin purified and crystallized in the presence of detergent. This structure, together with our previously determined 2.3-Å structure of the VCC water-soluble monomer, reveals in detail the architectural changes that occur within the channel region and accessory lectin domains during pore formation including substantial rearrangements of hydrogen-bonding networks in the pore-forming amphipathic loops. Interestingly, a ring of tryptophan residues forms the narrowest constriction in the transmembrane channel reminiscent of the phenylalanine clamp identified in anthrax protective antigen [Krantz BA, et al. (2005) Science 309:777-781]. Our work provides an example of a β-barrel PFT (β-PFT) for which soluble and assembled structures are available at high-resolution, providing a template for investigating intermediate steps in assembly.hemolysin | membrane protein | X-ray crystallography | virulence factor

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Pore formation: An ancient yet complex form of attack

Cited by 165 publications

References 135 publications

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

Crystal structure of the octameric pore of staphylococcal γ-hemolysin reveals the β-barrel pore formation mechanism by two components

Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore-forming toxins

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