Decloaking perforin, the protein assassin

Perforin punching pores through a cell membrane, allowing granzyme toxins to move into and destroy the cell. (Image credit: Mike Kuiper, VPAC)

When the immune system identifies a cell that needs to be eliminated, such as a virus-infected cell or cancer cell, natural killer cells descend and puncture the offending cell, injecting toxic enzymes to spell its doom.

This notion has been understood for over a century, but now researchers from Melbourne and London have identified the mechanism by which this process unfolds.

At the centre of this immune response is a crucial protein called perforin, which is responsible for forming a pore in the diseased cell.

“Perforin is our body’s weapon of cleansing and death,” said project leader Professor James Whisstock from Monash University.

“It breaks into cells that have been hijacked by viruses or turned into cancer cells and allows toxic enzymes in, to destroy the cell from within. Without it our immune system can’t destroy these cells. Now we know how it works, we can start to fine tune it to fight cancer, malaria and diabetes,” he said.

It is known that when perforin is functioning incorrectly it can either result in greater levels of malignancy, such as with leukaemia, or in autoimmune disorders where the body's immune system attacks itself.

Interestingly, perforin resembles the cellular weaponry employed by bacteria such as anthrax, listeria and streptococcus.

“The molecular structure has survived for close to two billion years, we think,” says Prof Joe Trapani, head of cancer immunology at Peter Mac.

Whisstock even hints that our immune system may have 'appropriated' the mechanism from bacteria long ago in our evolutionary past, turning the pathogen's arsenal against them.

The researchers used the Australian Synchrotron to determine the X-ray crystal structure of the protein along with cryo-electron microscopy reconstruction of the perforin pore. Together, these give a detailed picture of how the protein functions.

The researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute diseases such as cerebral malaria. And with the help of a $1 million grant from the Wellcome Trust they are working on potential inhibitors to suppress perforin and counter tissue rejection.

"One of the projects that we have at the moment is funded through the ARC Super Science Fellowship program, which is a more general program to look at using pore-forming proteins such as perforin to, if you like, deliver toxic cargoes into cells of our choice," said Whisstock on ABC radio.

The paper was published in Nature today (doi:10.1038/nature09518), and was a collaboration between researchers at Monash University, Birkbeck College, London and the Peter MacCullum Cancer Centre.

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