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.
Highlights
Plasma membrane acts as a semi-permeability barrier between the cell and the extracellular environment, and its integrity is essential for cell survival and sustainability.disruption of the plasma membrane is considered to be one of the ancient cellkilling mechanisms by which bacteria invade humans
3–4 monomers oligomerize on the membrane surface and simultaneously inserted into the membrane to form transmembrane pore with the membrane lipids rearrangement detected by differential scanning calorimetry and atomic force microscopy [75] but without a pre-pore intermediate state
Some unclassified pore-forming toxins (PFTs) orphans, such as the repeats-in-toxin (RTX) subfamily, represent a unique class of bacterial exoproteins possessing numerous glycine-rich repeat units (G–G–X–G–(N/D) –D–X–(L/I/V/W/Y/F)–X) at the C-terminus of each protein. This subfamily includesα-hemolysin (HlyA) from E. coli, Adenylate cyclasehemolysin (CyaA) from Bordetella pertussis [81], and the multifunctional autoprocessing repeats-in-toxin (MARTX) from A. hydrophila and other pathogens [82].These RTX motifs exhibit intrinsically elongated disordered coil in Apo state, while exhibit rigid fold in the calcium-binding state, which is involved in the calcium-dependent secretion process for unidirectional export through the secretory channel [83]
Summary
Plasma membrane acts as a semi-permeability barrier between the cell and the extracellular environment, and its integrity is essential for cell survival and sustainability. Pore-forming proteins (PFPs) are among such molecules that can alter membrane permeability, in which pore-forming toxins (PFTs) constitute the major class [1,2,3]. Upon binding to specific receptors (sugars, lipid, or proteins) in the membrane, PFPs (PFTs) oligomerize to form transmembrane pores with refined architecture, which alter membrane permeability and induce several responses in target cells. An increasing number of related pore-forming toxins from pathogens are being studied. Demonstrating their structure and implications on host-pathogen interaction helps to clearly understand the disease mechanism. We reviewed the structural mechanisms of pore formation and host-pathogen interaction of PFTs at an atomic level, contributing developing novel therapeutic strategies to fight infection targeting PFTs and/or host receptors interaction
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