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Lethal weapons

(Image: Darlyne A. Murawski/Getty)

We may be a step closer to understanding how some meat-eating fungi turned predator. It turns out that the edible oyster mushroom uses a special class of immune system proteins to kill its parasites – and possibly its prey. We carry similar proteins, as do many of our pathogens, and understanding their action could help us fight common diseases.

Most fungi are relatively peaceful, but a small number are carnivorous – perhaps less than 0.5 per cent of all species. Some use nooses to strangle passing nematode worms, others kill insects with lethal toxins. These toxins may include the pleurotolysin protein produced by the edible mushroom (Pleurotus ostreatus, according to Michelle Dunstone at Monash University in Melbourne, Australia.

Nanoscopic cookie cutter

Pleurotolysin isn’t your average protein. It belongs to a group of water-soluble proteins that can form pores in cell membranes. Individual molecules can behave like lego bricks, linking together in a rings of 13 on the surface of a target cell. Once the ring is complete, each molecule unravels downwards, punching through the cell membrane like a nanoscopic cookier cutter, creating an 8-nanometre-wide hole. If the hole doesn’t kill the cell directly other lethal molecules slip inside and finish the job.

“Proteins normally exist in just one form,” says Helen Saibil at Birkbeck, University of London. “It’s really unusual for them to switch from being water-soluble to sinking through a membrane. It’s quite a dramatic change.”

Video: Mushroom kills with cookie cutter trick

Saibil – working with Dunstone and colleagues – has now shown how that change happens in this protein. They froze the proteins at various stages in the process and examined the snapshots under an electron microscope.

The team also engineered additional proteins that would jam the pleurotolysin at certain points in its assembly, making it easier to capture snapshots of the entire process.

Human versions

It emerged that one particular region of the protein – TMH2 – is vital for the unravelling process that enables each molecule to punch through the membrane. That information could help us understand and even control the “cookie cutting” of pleurotolysin-like proteins in other species, the researchers say.

For instance, manipulating the human version – perforin – might help to stop immune cells from mistakenly attacking other cells in our bodies and triggering autoimmune conditions. Controlling the versions in bacteria such as Listeria and Streptococcus could help to tackle bacterial meningitis and pneumonia.

Pleurotolysin was a good version of the protein to study first, though, because it behaves much more simply than the human version, says Dunstone.

“Sometimes you get a good lego set where everything fits together and it’s easy to change things, and sometimes you get a set that is difficult to work with,” she says. “The human proteins are very difficult.”

Because different versions of the protein are very different at the molecular level, it will be tricky to apply the new knowledge to other species, says Vernon Carruthers at the University of Michigan in Ann Arbor.

Saibil says this is true in general, but she thinks the crucial unravelling mechanism may be similar in the mushroom and human version of the protein.

So has the oyster mushroom turned pleurotolysin from an immune system protein that helps it kill pathogens into a toxin that helps it kill nematode prey? It’s an idea that needs to be confirmed with experiments, says Dunstone, but it would make sense to repurpose an existing killer protein rather than evolve an entirely new one. “That happens time and again in nature,” she says.

Journal reference: PLoS Biology, DOI: 10.1371/journal.pbio.1002049

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