Pore-Forming Toxins in Membrane Dynamics

Pore-forming toxins (PFTs) constitute a diverse class of proteins that permeabilise lipid bilayers, serving roles in bacterial virulence, immune defence and intercellular signalling. They encompass families such as membrane attack complex/perforin (MACPF), cholesterol-dependent cytolysins (CDCs) and aerolysin-like toxins. Typically secreted as soluble monomers, PFTs bind target membranes through specific lipid or receptor interactions, undergo oligomerisation into prepore assemblies and then refold α-helical segments into transmembrane β-hairpins that assemble into a β-barrel pore. The resulting transmembrane channel, varying in stoichiometry and diameter, disrupts membrane integrity to induce lysis or sublytic signalling. Host factors such as glycan scaffolds, complement regulators or pH modulate pore assembly, while membrane composition influences insertion kinetics. Beyond pathogenesis, PFTs are harnessed in immunotherapy and nanotechnology, illustrating their utility as molecular tools. Contemporary microscopy and biophysical methods have begun to unravel the dynamic conformational transitions and energetic landscape governing pore formation, revealing mechanisms conserved across kingdoms and shedding light on therapeutic strategies to modulate membrane permeability.

Research from Nature Portfolio

Recent structural and biophysical studies have elucidated how host regulators intercept complement-derived pores and how the membrane attack complex (MAC) breaches lipid bilayers. High-resolution cryo-electron microscopy structures of complement precursors bound to an inhibitory receptor reveal how membrane factors redirect β-hairpins to arrest pore formation. Complementary molecular dynamics simulations show that lipid composition influences this dual blockade of pore insertion and polymerisation. Meanwhile, combined cryo-EM and flicker spectroscopy analyses of the MAC pore have demonstrated a two-stage mechanism for membrane disruption: early components lower the bending energy of the outer leaflet, whereas later subunits traverse both leaflets to stiffen the bilayer. These studies highlight the plasticity of β-barrel pores, the role of glycan scaffolds in stabilising asymmetric assemblies and the energetic transitions that underpin host defence and tissue homeostasis.

Pore-Forming Toxins in Membrane Dynamics publication trend

The graph below shows the total number of articles in pore-forming toxins in membrane dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

β-barrel pore: Cylindrical channel formed by β-strands traversing the lipid bilayer.

Oligomerisation: Association of individual protein monomers into a multimeric complex.

Prepore: Membrane-bound intermediate prior to conformational insertion of β-hairpins.

Membrane attack complex (MAC): Complement-derived assembly that forms lytic pores on target membranes.

Cholesterol-dependent cytolysin (CDC): Family of bacterial toxins requiring membrane cholesterol for pore formation.

Transmembrane β-hairpin: Pair of β-strands refolded from soluble helices to span the lipid bilayer.

References

1. Structural basis for membrane attack complex inhibition by CD59. Nature Communications (2023).
2. CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers. Nature Communications (2018).
3. Complement C7 and clusterin form a complex in circulation. Frontiers in Immunology (2024).
4. Stepwise visualization of membrane pore formation by suilysin, a bacterial cholesterol-dependent cytolysin. eLife (2014).
5. Perforin-2 is essential for intracellular defense of parenchymal cells and phagocytes against pathogenic bacteria. eLife (2015).