Pore forming toxin, α-hemolysin

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α-Hemolysin from Staphlococcus aureus is a pore-forming toxin made of seven repeats of an identical monomer arranged in a ring. The structural basis of the toxic activity was readily revealed when the structure of the ring was solved.

Contents

ALPHA-HEMOLYSIN FROM STAPHYLOCOCCUS AUREUS

Publication Abstract from PubMed

The structure of the Staphylococcus aureus alpha-hemolysin pore has been determined to 1.9 A resolution. Contained within the mushroom-shaped homo-oligomeric heptamer is a solvent-filled channel, 100 A in length, that runs along the sevenfold axis and ranges from 14 A to 46 A in diameter. The lytic, transmembrane domain comprises the lower half of a 14-strand antiparallel beta barrel, to which each protomer contributes two beta strands, each 65 A long. The interior of the beta barrel is primarily hydrophilic, and the exterior has a hydrophobic belt 28 A wide. The structure proves the heptameric subunit stoichiometry of the alpha-hemolysin oligomer, shows that a glycine-rich and solvent-exposed region of a water-soluble protein can self-assemble to form a transmembrane pore of defined structure, and provides insight into the principles of membrane interaction and transport activity of beta barrel pore-forming toxins.

Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore., Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE, Science. 1996 Dec 13;274(5294):1859-66. PMID:8943190

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Background

Staphylococcus aureus is often pathogenic to humans and relies on several virulence factors in the course of the infections. α-hemolysin is one such virulencce factor that forms pores in target cells[1], similar to other hemolsyins.

About this Structure

 

The α-hemolysin oligomer

α-hemolysin (7ahl) is a 7 chain structure of protein sequences from Staphylococcus aureus.

Each chain in the oligomeric complex is an identical monomer; the other monomers are translucent to emphasize one of the seven monomers. Note the seven-fold rotational symmetry. Fancy, high-quality cartoons on/off.

Seven monomers come together in a ring, with

each monomer donating 2 β-hairpins to form the stalk that protrudes from the bottom of the structure. Fancy, high-quality cartoons on/off.

 

α-hemolysin interaction with the membrane

At around 2.8 nm in height, α-hemolysin's stalk is perfectly designed to span the plasma membrane of eukaryotic cells (ca. 2.5 nm or 25 Å).

Unlike the polar surface of more typical proteins, the stalk is hydrophobic, and is instead lipophilic or preferring to be in a lipid environment.

Contrast the hydrophobic stalk with the rest of the structure which is largely polar since it would sit outside the cell.
KEY: Polar Hydrophobic

To help give a better idea of how α-hemolysin interacts with the membrane lipid bilayer, a slab representative of the hydrophobic core of the lipid bilayer as calculated by the Orientations of Proteins in Membranes database(University of Michigan, USA) is shown as a cylinder with the red patch indicating the boundary closet to the outside of the cell and the blue patch indicating the boundary closest to the inside of the cell.

 

 

The α-hemolysin pore

Displaying the surface illustrates clearly that there is a tunnel down the middle of the heptamer that leads to the formation of pores in the cell membrane, which is the structural basis for why these are toxins. Such pores are expectedly detrimental to the cell, allowing exodus of critical molecules, destroying the established membrane potential and ionic gradients, and contributing to osmotic swelling. Fancy, high-quality cartoons on/off.

Hemolysin (7ahl), resolution 1.89Å.

Drag the structure with the mouse to rotate

Initial scene                                                   

Use of α-hemolysin in DNA sequencing technology

In 1996, researchers from Harvard University and the University of California at Santa Cruz, including Daniel Branton, David Deamer and John Kasianowicz showed that the pore structure formed by α-hemolysin could be used to pass a single strand of DNA through a nanopore [2]. This was later linked to an exonuclease and a detection mechanism for residency of individual nucleotides in the base of pore to ultimately form the basis of sequencing technology finally offered by Oxford Nanopore, although the specifics of the current generation of the technology may be different [3][4].

PDB entry

7ahl is a 7 chain structure of sequences from Staphylococcus aureus. Full crystallographic information is available from OCA.

Reference for the structure

  • Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H, Gouaux JE. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science. 1996 Dec 13;274(5294):1859-66. PMID:8943190

Notes and Literature References

  1. Menestrina G, Dalla Serra M, Comai M, Coraiola M, Viero G, Werner S, Colin DA, Monteil H, Prevost G. Ion channels and bacterial infection: the case of beta-barrel pore-forming protein toxins of Staphylococcus aureus. FEBS Lett. 2003 Sep 18;552(1):54-60. PMID:12972152
  2. Kasianowicz JJ, Brandin E, Branton D, Deamer DW. Characterization of individual polynucleotide molecules using a membrane channel. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13770-3. PMID:8943010
  3. Nanopore sequencing: Towards the 15-minute genome. The Economist. Technology Quarterly: Q1 2011. Mar 10th 2011. http://www.economist.com/node/18304268
  4. Pennisi E. Genome sequencing. Search for pore-fection. Science. 2012 May 4;336(6081):534-7. PMID:22556226 doi:10.1126/science.336.6081.534

3D structures of hemolysin

see, Hemolysin

See Also

Additional Literature and Resources


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