Perforin packs a punch

The human immune system’s assassin – the protein perforin – has been seen in action for the first time, and it packs quite a punch

Perforin punches holes in and kills rogue cells – cancerous cells or those invaded by viruses – says research from the UK and Australia. Toxic enzymes enter the holes and destroy the cells – if perforin doesn’t do its job properly, the body can’t fight infected cells and mouse models show defective performin leads to an increase in malignancy, particularly leukaemia.

“Perforin is a powerful bullet in the arsenal of our immune system – without it we could not deal with the thousand of rogue cells that turn up in our bodies through our lives,” said Professor Helen Saibil from Birkbeck College.

The first observations that the immune system could punch holes in target cells was made by Nobel Laureate Jules Bordet 110 years ago, but scientists had to wait for advances in structural molecular biology to find out how.

Saibil and colleagues were able to take electron microscope images of a ring of perforin molecules clustered together to form a hole in a cell membrane. A team of scientists from Monash University in Australia were able to uncover the detailed structure of a single perforin molecule using the Australian Synchrotron.

The research confirmed that the important parts of the perforin molecule are similar to those toxins deployed by bacteria like anthrax, listeria and streptococcus. It shows that this method of punching holes in cell membranes is quite ancient in evolution.

“Perforin is our body’s weapon of cleansing and death,” said Monash’s Professor James Whisstock, “Now we know how it works, we can start to fine tune it to fight cancer, malaria and diabetes.”

Perforin is also the culprit when the wrong cells are marked for elimination in autoimmune disease or in tissue rejection following a bone marrow transplant. Researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute disease. A Wellcome Trust grant of £600,000 is also enabling them to work on inhibitors to suppress perforin and counter tissue rejection.

“New technologies in microscopy and synchrotron experiments have opened up tremendous opportunities for molecular biologists,” said Professor Douglass Kell, Chief Executive of the BBSRC who funded Birkbeck researchers, “This is a great example where the knowledge we gain about the normal structure and function of a molecule has the potential to underpin important developments in our health and well being.”