Structural Basis of the Pore-Forming Toxin/Membrane Interaction

Abstract

With the rapid growth of antibiotic-resistant bacteria, it is urgent to develop alternative therapeutic strategies. Pore-forming toxins (PFTs) belong to the largest family of virulence factors of many pathogenic bacteria and constitute the most characterized classes of pore-forming proteins (PFPs). Recent studies revealed the structural basis of several PFTs, both as soluble monomers, and transmembrane oligomers. Upon interacting with host cells, the soluble monomer of bacterial PFTs assembles into transmembrane oligomeric complexes that insert into membranes and affect target cell-membrane permeability, leading to diverse cellular responses and outcomes. Herein we have reviewed the structural basis of pore formation and interaction of PFTs with the host cell membrane, which could add valuable contributions in comprehensive understanding of PFTs and searching for novel therapeutic strategies targeting PFTs and interaction with host receptors in the fight of bacterial antibiotic-resistance.

Keywords: membrane interaction; pore-forming toxin; structure.

Figure 1

Structural characteristics of pore-formation specific for each structural family. Representative monomer and pore structure of α-PFTs and β-PFT members are illustrated. For α-PFTs, upon binding to the membrane, α-helices undergo a conformational change to insert into the membrane and form membrane pore. For β-PFTs, monomer β-PFT first assembles in a pre-stem loop, and inserts into the membrane to form a partial β-barrel, and then combines with the other protomers to form a complete β-barrel. (A). α-PFTs: soluble and membrane pore complex, adopted from PDBs 1COL, 1A87, 1CII, 2I88, 1IAZ, 1GWY, 4TSL, 1QOY, 4K1P, 2NRJ, 6JLC, 2COL, 4TSY. (B). β-PFTs: soluble and membrane pore complex, adopted from PDBs 4YHD, 4Q7G, 1XEZ, 2YGT, 1UYJ, 3C0M, 3ZIW, 3ZXD, 4MKO, 1PFO, 1S3R, 4HSC, 5AOF, 2QP2, 6RB9.

Figure 2

General mechanism of membrane pore formation by the bacterial PFTs. The diagram schematic presents the pore formation pathways of pore-forming toxins (PFTs). Soluble PFTs are recruited to the plasma membrane surface by binding to sugar, lipids or receptors molecules. The PFTs concentrate on the membrane surface, and then two pathways are alternatively taken to form the final membrane pore. In one pathway applicable to most β-PFTs, PFTs oligomerize on the membrane surface, and produce a pre-pore intermediate structure. In another pathway applicable to most α-PFTs, PFTs oligomerize and insert into the plasma membrane coordinately by a mechanism of sequential oligomerization, which forms a partial pore or complete pores, and both are active. In both pathways of α-PFT and β-PFT, formed transmembrane pores present distinct characteristics, and trigger cell responses.