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Structural Research of Alpha-helical Pore-forming Toxins

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Pore-forming toxins (PFTs) are important components of the molecular offensive and defensive machinery in many species. In eukaryotes, PFTs are primarily involved in the innate immune response, whilst in prokaryotes, they constitute the major virulence factor group of many pathogenic bacteria. By puncturing holes in the membrane, pathogenic PFTs can disrupt the osmotic balance of host target cells or insert secondary intracellular toxins through the pores formed in the membrane. Many pathogenic bacteria, including strains that are highly resistant to antibiotics, use PFTs in their invasive arsenal. This makes them attractive targets for developing therapies to reduce the acquired resistance that occurs with conventional antimicrobial therapy.

PFTs are produced in a soluble, often monomeric form and recognize target cells by binding to specific receptors, thereby concentrating the protein to the membrane surface prior to exposure of transmembrane hydrophobic regions, oligomerization, and membrane insertion. Depending on the secondary structure of the membrane assembly, PFTs can be classified into α-PFTs, which use amphipathic helical loops to construct the pore, or β-PFTs, in which the β-barrel is employed to traverse the membrane.

Structure of soluble and pore form SmhB.Figure 1. Structure of soluble and pore form SmhB. (Churchill-Angus A M, et al., 2021)

ProteinOrganismMethodResolutionPDB Entry ID
Cytolysin A pore (expressed in Escherichia coli)Escherichia coli K-12X-ray diffraction3.29 Å2WCD
AhlB pore of the tripartite alpha-pore forming toxin (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction2.94 Å6GRJ
Pre-pore AhlB (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction2.55 Å6H2F
Soluble AhlB (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction2.33 Å6GRK
Soluble AhlC form 1 (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction2.35 Å6H2E
Soluble AhlC form 2 (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction2.62 Å6H2D
Soluble AhlC triple head mutant (expressed in Escherichia coli)Aeromonas hydrophilaX-ray diffraction1.92 Å6R1J
SmhB pore of the tripartite alpha-pore forming toxin (expressed in Escherichia coli)Serratia marcescensX-ray diffraction6.98 Å7A0G
Soluble SmhA crystal form 1 (expressed in Escherichia coli)Serratia marcescensX-ray diffraction2.98 Å7A26
Soluble SmhA crystal form 2 (expressed in Escherichia coli)Serratia marcescensX-ray diffraction2.57 Å7A27
Soluble SmhB (expressed in Escherichia coli)Serratia marcescensX-ray diffraction1.84 Å6ZZ5
Soluble SmhB crystal form 2 (expressed in Escherichia coli)Serratia marcescensX-ray diffraction1.86 Å6ZZH
Full-length Cry6Aa (expressed in Pseudomonas fluorescens)Bacillus thuringiensisX-ray diffraction2.70 Å5KUD
Trypsin activated Cry6Aa (expressed in Pseudomonas fluorescens)Bacillus thuringiensisX-ray diffraction2.00 Å5KUC
FraC eukaryotic pore-forming toxin from sea anemoneActinia fragaceaX-ray diffraction1.80 Å3LIM
FraC with lipids (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction3.14 Å4TSY
Soluble FraC monomer (I) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction1.70 Å3VWI
Soluble FraC monomer (II) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction2.10 Å3W9P
FraC dimer with phosphorylcholine (I) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction1.60 Å4TSL
FraC dimer with phosphorylcholine (II) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction1.57 Å4TSN
FraC with DHPC bound (I) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction2.30 Å4TSO
FraC with DHPC bound (II) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction2.15 Å4TSP
FraC with DHPC bound (III) (expressed in Escherichia coli)Actinia fragaceaX-ray diffraction1.60 Å4TSQ
Hexameric anti-microbial peptide channel dermcidinHomo sapiensX-ray diffraction2.49 Å2YMK
TcdA1 (expressed in Escherichia coli)Photorhabdus luminescensX-ray diffraction3.50 Å4O9Y
TcdB2-TccC3 (expressed in Escherichia coli)Photorhabdus luminescensX-ray diffraction2.17 Å4O9X
Tc toxin TcdA1 in its pore state (obtained by flexible fitting) (expressed in Escherichia coli)Photorhabdus luminescensCryo-EM single particle analysis3.46 Å5LKH
Tc toxin TcdA1 in its pore state (expressed in Escherichia coli)Photorhabdus luminescensCryo-EM single particle analysis3.46 Å5LKI
Tc holotoxin pore (expressed in Escherichia coli)Photorhabdus luminescensCryo-EM single particle analysis3.40 Å6SUF
Tc holotoxin pore, TccC3-D651A mutant (expressed in Escherichia coli)Photorhabdus luminescensCryo-EM single particle analysis3.40 Å6SUE
Listeriolysin O pore-forming toxinListeria monocytogenesX-ray diffraction2.15 Å4CDB
XaxAB pore complex (expressed in Escherichia coli)Xenorhabdus nematophilaCryo-EM single particle analysis4.00 Å6GY6
XaxA monomer (expressed in Escherichia coli)Xenorhabdus nematophilaX-ray diffraction2.50 Å6GY8
XaxB monomer (expressed in Escherichia coli)Xenorhabdus nematophilaX-ray diffraction3.40 Å6GY7
VacA vacuolating cytotoxin A oligomeric assembly OA-1Helicobacter pyloriCryo-EM single particle analysis3.20 Å6NYF
VacA oligomeric assembly OA-2aHelicobacter pyloriCryo-EM single particle analysis3.90 Å6NYG
VacA oligomeric assembly OA-2bHelicobacter pyloriCryo-EM single particle analysis3.20 Å6NYJ
VacA oligomeric assembly OA-2cHelicobacter pyloriCryo-EM single particle analysis3.70 Å6NYL
VacA oligomeric assembly OA-2dHelicobacter pyloriCryo-EM single particle analysis3.60 Å6NYM
VacA oligomeric assembly OA-2eHelicobacter pyloriCryo-EM single particle analysis3.50 Å6NYN
VacA hexamerHelicobacter pyloriCryo-EM single particle analysis3.80 Å6ODY
RhopH complex in soluble formPlasmodium falciparumCryo-EM single particle analysis2.92 Å7KIY
Vip3Bc1 tetramer (expressed in Pseudomonas fluorescens)Bacillus thuringiensisCryo-EM single particle analysis3.90 Å6YRF
Vip3Bc1 tetramer in processed, activated state (expressed in Pseudomonas fluorescens)Bacillus thuringiensisCryo-EM single particle analysis4.80 Å6YRG
Vip3Bc1 tetramer in processed, activated state (expressed in Pseudomonas fluorescens)Bacillus thuringiensisCryo-EM single particle analysis4.75 Å7NTX

Table 1. Structural Research of Alpha-helical Pore-forming Toxins.

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References

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  4. Dementiev A, et al. The pesticidal Cry6Aa toxin from Bacillus thuringiensis is structurally similar to HlyE-family alpha pore-forming toxins. BMC Biology. 2016, 14(1): 1-16.
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