Bacterial gasdermins reveal an ancient mechanism of cell death

Ancient origin of cell death Gasdermins are cell death proteins in mammals that form membrane pores in response to pathogen infection. Johnson et al . report that diverse bacteria encode structural and functional homologs of mammalian gasdermins. Like their mammalian counterparts, bacterial gasdermins are activated by caspase-like proteases, oligomerize into large membrane pores, and defend against pathogen—in this case, bacteriophage—infection. Proteolytic activation occurs through the release of a short inhibitory peptide, and many bacterial gasdermins are lipidated to facilitate membrane pore formation. Pyroptotic cell death, a central component of mammalian innate immunity, thus has a shared origin with an ancient antibacteriophage defense system. —SMH

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Computational studies of peptide-induced membrane pore formation

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2016.0219 ◽

2017 ◽

Vol 372 (1726) ◽

pp. 20160219 ◽

Cited By ~ 20

Author(s):

Richard Lipkin ◽

Themis Lazaridis

Keyword(s):

Pore Formation ◽

Coarse Grained ◽

Future Research ◽

Implicit Solvent ◽

Computational Studies ◽

Membrane Pore ◽

Membrane Pores ◽

Solvent Models ◽

Future Research Directions ◽

Implicit Solvent Models

A variety of peptides induce pores in biological membranes; the most common ones are naturally produced antimicrobial peptides (AMPs), which are small, usually cationic, and defend diverse organisms against biological threats. Because it is not possible to observe these pores directly on a molecular scale, the structure of AMP-induced pores and the exact sequence of steps leading to their formation remain uncertain. Hence, these questions have been investigated via molecular modelling. In this article, we review computational studies of AMP pore formation using all-atom, coarse-grained, and implicit solvent models; evaluate the results obtained and suggest future research directions to further elucidate the pore formation mechanism of AMPs. This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.

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Bacterial gasdermins reveal an ancient mechanism of cell death

10.1101/2021.06.07.447441 ◽

2021 ◽

Author(s):

Alex G Johnson ◽

Tana Wein ◽

Megan L Mayer ◽

Brianna Duncan-Lowey ◽

Erez Yirmiya ◽

...

Keyword(s):

Cell Death ◽

Pore Formation ◽

Membrane Integrity ◽

Lipid Modification ◽

Site Specific ◽

Prokaryotic Cell ◽

Inactive State ◽

Membrane Pores ◽

Regulated Cell Death ◽

Peptide Release

Gasdermin proteins form large membrane pores in human cells that release immune cytokines and induce lytic cell death. Gasdermin pore formation is triggered by caspase-mediated cleavage during inflammasome signaling and is critical for defense against pathogens and cancer. Here we discover gasdermin homologs encoded in bacteria that execute prokaryotic cell death. Structures of bacterial gasdermins reveal a conserved pore-forming domain that is stabilized in the inactive state with a buried lipid modification. We demonstrate that bacterial gasdermins are activated by dedicated caspase-like proteases that catalyze site-specific cleavage and removal of an inhibitory C-terminal peptide. Release of autoinhibition induces the assembly of >200 Å pores that form a mesh-like structure and disrupt membrane integrity. These results demonstrate that caspase-mediated activation of gasdermins is an ancient form of regulated cell death shared between bacteria and animals.

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Effect of helical kink in antimicrobial peptides on membrane pore formation

eLife ◽

10.7554/elife.47946 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Alzbeta Tuerkova ◽

Ivo Kabelka ◽

Tereza Králová ◽

Lukáš Sukeník ◽

Šárka Pokorná ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Pore Formation ◽

Molecular Level ◽

Helical Peptides ◽

Membrane Pore ◽

Bacterial Membranes ◽

Membrane Pores ◽

Helical Peptide ◽

Toroidal Pore ◽

The Right

Every cell is protected by a semipermeable membrane. Peptides with the right properties, for example Antimicrobial peptides (AMPs), can disrupt this protective barrier by formation of leaky pores. Unfortunately, matching peptide properties with their ability to selectively form pores in bacterial membranes remains elusive. In particular, the proline/glycine kink in helical peptides was reported to both increase and decrease antimicrobial activity. We used computer simulations and fluorescence experiments to show that a kink in helices affects the formation of membrane pores by stabilizing toroidal pores but disrupting barrel-stave pores. The position of the proline/glycine kink in the sequence further controls the specific structure of toroidal pore. Moreover, we demonstrate that two helical peptides can form a kink-like connection with similar behavior as one long helical peptide with a kink. The provided molecular-level insight can be utilized for design and modification of pore-forming antibacterial peptides or toxins.

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Conformational Switch Driven Membrane Pore Formation byMycobacteriumSecretory Protein MPT63 Induces Macrophage Cell Death

ACS Chemical Biology ◽

10.1021/acschembio.9b00327 ◽

2019 ◽

Vol 14 (7) ◽

pp. 1601-1610 ◽

Cited By ~ 6

Author(s):

Achinta Sannigrahi ◽

Indrani Nandi ◽

Sayantani Chall ◽

Junaid Jibran Jawed ◽

Animesh Halder ◽

...

Keyword(s):

Cell Death ◽

Pore Formation ◽

Macrophage Cell ◽

Conformational Switch ◽

Membrane Pore

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Effect of Helical Kink in Antimicrobial Peptides on Membrane Pore Formation

10.1101/641514 ◽

2019 ◽

Author(s):

Alzbeta Tuerkova ◽

Ivo Kabelka ◽

Tereza Králová ◽

Lukáš Sukeník ◽

Šárka Pokorná ◽

...

Keyword(s):

Antimicrobial Peptides ◽

Pore Formation ◽

Molecular Level ◽

Helical Peptides ◽

Membrane Pore ◽

Bacterial Membranes ◽

Membrane Pores ◽

Helical Peptide ◽

Toroidal Pore ◽

The Right

AbstractEvery cell is protected by a semipermeable membrane. Peptides with the right properties, e.g. Antimicrobial peptides (AMPs), can disrupt this protective barrier by formation of leaky pores. Unfortunately, matching peptide properties with their ability to selectively form pores in bacterial membranes remains elusive. In particular, the proline/glycine kink in helical peptides was reported to both increase and decrease antimicrobial activity. We used computer simulations and fluorescence experiments to show that a kink in helices affects the formation of membrane pores by stabilizing toroidal pores but disrupting barrel-stave pores. The position of the proline/glycine kink in the sequence further controls the specific structure of toroidal pore. Moreover, we demonstrate that two helical peptides can form a kink-like connection with similar behavior as one long helical peptide with a kink. The provided molecular-level insight can be utilized for design and modification of pore forming antibacterial peptides or toxins.

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GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death

The EMBO Journal ◽

10.15252/embj.201694696 ◽

2016 ◽

Vol 35 (16) ◽

pp. 1766-1778 ◽

Cited By ~ 322

Author(s):

Lorenzo Sborgi ◽

Sebastian Rühl ◽

Estefania Mulvihill ◽

Joka Pipercevic ◽

Rosalie Heilig ◽

...

Keyword(s):

Cell Death ◽

Pore Formation ◽

Membrane Pore

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Effect of arginine-rich cell penetrating peptides on membrane pore formation and life-times: a molecular simulation study

Physical Chemistry Chemical Physics ◽

10.1039/c4cp02211d ◽

2014 ◽

Vol 16 (38) ◽

pp. 20785-20795 ◽

Cited By ~ 37

Author(s):

Delin Sun ◽

Jan Forsman ◽

Mikael Lund ◽

Clifford E. Woodward

Keyword(s):

Molecular Simulation ◽

Simulation Study ◽

Pore Formation ◽

Molecular Simulations ◽

Cell Penetrating Peptides ◽

Flip Flop ◽

Membrane Pore ◽

Membrane Pores ◽

Cell Penetrating

Molecular simulations show that arginine-rich peptides can stabilize transient membrane pores induced by lipid flip-flop.

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Membrane perforation by the pore-forming toxin pneumolysin

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1904304116 ◽

2019 ◽

Vol 116 (27) ◽

pp. 13352-13357 ◽

Cited By ~ 24

Author(s):

Martin Vögele ◽

Ramachandra M. Bhaskara ◽

Estefania Mulvihill ◽

Katharina van Pee ◽

Özkan Yildiz ◽

...

Keyword(s):

Lipid Membranes ◽

Pore Formation ◽

Line Tension ◽

Coarse Grained ◽

Membrane Pore ◽

Membrane Pores ◽

Membrane Perforation ◽

Membrane Spanning ◽

Dynamics Simulations ◽

Key Steps

Pneumolysin (PLY), a major virulence factor ofStreptococcus pneumoniae, perforates cholesterol-rich lipid membranes. PLY protomers oligomerize as rings on the membrane and then undergo a structural transition that triggers the formation of membrane pores. Structures of PLY rings in prepore and pore conformations define the beginning and end of this transition, but the detailed mechanism of pore formation remains unclear. With atomistic and coarse-grained molecular dynamics simulations, we resolve key steps during PLY pore formation. Our simulations confirm critical PLY membrane-binding sites identified previously by mutagenesis. The transmembrane β-hairpins of the PLY pore conformation are stable only for oligomers, forming a curtain-like membrane-spanning β-sheet. Its hydrophilic inner face draws water into the protein–lipid interface, forcing lipids to recede. For PLY rings, this zone of lipid clearance expands into a cylindrical membrane pore. The lipid plug caught inside the PLY ring can escape by lipid efflux via the lower leaflet. If this path is too slow or blocked, the pore opens by membrane buckling, driven by the line tension acting on the detached rim of the lipid plug. Interestingly, PLY rings are just wide enough for the plug to buckle spontaneously in mammalian membranes. In a survey of electron cryo-microscopy (cryo-EM) and atomic force microscopy images, we identify key intermediates along both the efflux and buckling pathways to pore formation, as seen in the simulations.

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