Challenges and approaches to studying pore-forming proteins

Benton, Joshua T; Bayly-Jones, Charles

doi:10.1042/bst20210706

Cited by 10 publications

(9 citation statements)

References 165 publications

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“…However, in the case of PFTs, additional challenges are posed by the highly dynamic nature of their membrane insertion process. Indeed, the complex structural rearrangements necessary for the transition from monomer to fully assembled pore has impeded full characterisation of the pore formation process [107,202,203]. Furthermore, members of several toxin families, such as CDC and RTX, often form arcs and incomplete pores, with the mixture of species further complicating structural resolution [107,130].…”

Section: Discussionmentioning

confidence: 99%

“…AFM has been used successfully to investigate the dynamics of pore assembly for CDC and RTX PFTs [130,204] and could be further employed in future studies with other families. More recently, the use of microfluidics devices for grid preparation in combination with time-resolved cryo-EM has shown incredible potential for studying dynamic conformational changes and heterogeneous structures [202,[205][206][207][208]. These approaches offer great promise for future study of the structural rearrangements necessary for PFT pore formation.…”

Section: Discussionmentioning

confidence: 99%

“…The use of detergents and the introduction of styrene-maleic acid polymers (SMALPs), nanodiscs and amphipols, which mimic the membrane environment, have improved the overall stability of proteins and protein complexes. This has contributed to increased success of structural approaches, in particular cryo-EM analysis [202]. However, in the case of PFTs, additional challenges are posed by the highly dynamic nature of their membrane insertion process.…”

Section: Discussionmentioning

confidence: 99%

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Bacterial pore-forming toxins

Ulhuq

Mariano

2022

Microbiology

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Pore-forming toxins (PFTs) are widely distributed in both Gram-negative and Gram-positive bacteria. PFTs can act as virulence factors that bacteria utilise in dissemination and host colonisation or, alternatively, they can be employed to compete with rival microbes in polymicrobial niches. PFTs transition from a soluble form to become membrane-embedded by undergoing large conformational changes. Once inserted, they perforate the membrane, causing uncontrolled efflux of ions and/or nutrients and dissipating the protonmotive force (PMF). In some instances, target cells intoxicated by PFTs display additional effects as part of the cellular response to pore formation. Significant progress has been made in the mechanistic description of pore formation for the different PFTs families, but in several cases a complete understanding of pore structure remains lacking. PFTs have evolved recognition mechanisms to bind specific receptors that define their host tropism, although this can be remarkably diverse even within the same family. Here we summarise the salient features of PFTs and highlight where additional research is necessary to fully understand the mechanism of pore formation by members of this diverse group of protein toxins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Bacterial pore-forming toxins

Ulhuq

Mariano

2022

Microbiology

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“…PFPs are widely distributed in all kingdoms of life, which have long been recognized as either pore-forming toxin for microbial infection or host immune executors (11, 39, 40). Specially, the knowledge of these PFPs derived from animals and plants is mainly focused on their roles in cell death.…”

Section: Discussionmentioning

confidence: 99%

Pore-forming protein βγ-CAT drives extracellular nutrient scavenging under cell starvation

Liu

Shi

et al. 2022

Preprint

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Nutrient acquisition is essential for cells. βγ-CAT is a pore-forming protein (PFP) and trefoil factor complex assembled under tight regulation identified in toad Bombina maxima. Here, we reported that B. maxima cells secreted βγ-CAT under glucose and glutamine deficiency to scavenge extracellular proteins for their nutrient supply and survival. AMP-activated kinase signaling positively regulated the expression and secretion of βγ-CAT. The PFP complex promoted albumin and ovalbumin uptake through endolysosomal pathways. Elevated intracellular amino acids, enhanced ATP production, and eventually prolonged cell survival were observed in the presence of βγ-CAT and extracellular albumin or ovalbumin. Liposome assays indicated that high concentration of ATP (around 1–5 mM) negatively regulated the opening of βγ-CAT channels. Collectively, these results uncovered that βγ-CAT is an essential element in cell nutrient scavenging under cell starvation by driving vesicular uptake of extracellular proteins, providing a new paradigm for PFPs in cell nutrient acquisition and metabolic flexibility.

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“…Pore-forming proteins (PFPs) and toxins are not restricted in the pathogenic bacteria only. These membrane-damaging proteins are documented in all the domains of life ( Benton and Bayly-Jones, 2021 ). For example, the effector functions of the immune system of the higher vertebrates including that of humans employ a number of PFPs ( Krawczyk et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Curcumin Inhibits Membrane-Damaging Pore-Forming Function of the β-Barrel Pore-Forming Toxin Vibrio cholerae Cytolysin

et al. 2022

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Vibrio cholerae cytolysin (VCC) is a β-barrel pore-forming toxin (β-PFT). Upon encountering the target cells, VCC forms heptameric β-barrel pores and permeabilizes the cell membranes. Structure-function mechanisms of VCC have been extensively studied in the past. However, the existence of any natural inhibitor for VCC has not been reported yet. In the present study, we show that curcumin can compromise the membrane-damaging activity of VCC. Curcumin is known to modulate a wide variety of biological processes and functions. However, the application of curcumin in the physiological scenario often gets limited due to its extremely poor solubility in the aqueous environment. Interestingly, we find that VCC can associate with the insoluble fraction of curcumin in the aqueous medium and thus gets separated from the solution phase. This, in turn, reduces the availability of VCC to attack the target membranes and thus blocks the membrane-damaging action of the toxin. We also observe that the soluble aqueous extract of curcumin, generated by the heat treatment, compromises the pore-forming activity of VCC. Interestingly, in the presence of such soluble extract of curcumin, VCC binds to the target membranes and forms the oligomeric assembly. However, such oligomers appear to be non-functional, devoid of the pore-forming activity. The ability of curcumin to bind to VCC and neutralize its membrane-damaging activity suggests that curcumin has the potential to act as an inhibitor of this potent bacterial β-PFT.

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Challenges and approaches to studying pore-forming proteins

Cited by 10 publications

References 165 publications

Bacterial pore-forming toxins

Bacterial pore-forming toxins

Pore-forming protein βγ-CAT drives extracellular nutrient scavenging under cell starvation

Curcumin Inhibits Membrane-Damaging Pore-Forming Function of the β-Barrel Pore-Forming Toxin Vibrio cholerae Cytolysin

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