'Bullet' structure reveals how the immune system keeps rogue cells in check
01 November 2010
Over 110 years ago, Nobel Laureate Jules Bordet was the first to notice that the human immune system was capable of punching holes in target cells. However, we have had to wait for the latest advances in structural molecular biology to find out exactly how this happens.
Perforin is a key component in the arsenal of 'killer' cells in the immune system. It is released by T lymphocytes (T cells) and natural killer cells (NK cells) when they recognise that a target cell may have become harmful to the body. Punching holes in the target cells allows toxic enzymes to get in and destroy the wayward cells.
We know that this process is important because if perforin is defective, as in some hereditary diseases, the body can't fight infected cells. There is evidence from mouse studies that defective perforin can lead to a rise in cancer, particularly leukaemia.
Researchers from Monash University and the Peter MacCallum Cancer Centre, both in Melbourne, and Birkbeck College in London collaborated on the ten-year study of the deadly protein.
Professor Helen Saibil, who led the UK team at Birkbeck College, said: "Perforin is a key weapon in our immune artillery - without it we could not deal with the thousands of rogue cells that turn up in our bodies throughout our lives. What we wanted to know was what does perforin look like, what movements does it make and how? To do this, we had to find out its molecular structure and function."
The structure was revealed by combining information about a single perforin molecule - visualised using the Australian Synchrotron - with electron microscope images of a ring of perforin molecules clustered together to form a hole in a cell membrane.
"Perforin is our body's weapon of cleansing," said Project Leader Professor James Whisstock from Monash University. "Now we know how it works, we can start to fine tune it to fight cancer, malaria and diabetes."
Professor Joe Trapani, co-Head of the Cancer Immunology Program at the Peter MacCallum Cancer Centre, has been studying the mechanism of the immune system's killer cells since 1985. He said: "Until now, perforin has been a real black box. No one has really known how it all fits together to form a pore. And that's really the point of this paper. That's what we've cracked."
Perforin is also the culprit when the wrong cells are marked for elimination, either in autoimmune disease conditions, such as early onset diabetes, or in tissue rejection following bone marrow transplantation. The researchers are now investigating ways to boost perforin for more effective cancer protection and therapy for acute viral diseases. With the help of a £600 thousand grant from the Wellcome Trust, they are working on potential inhibitors to suppress perforin and counter tissue rejection.
Another interesting finding is that the important parts of the perforin molecule are quite similar to those toxins deployed by bacteria such as anthrax, listeria and streptococcus, showing that this method of making holes in cell membranes is quite ancient in evolution. "The molecular structure has survived for close to two billion years, we think," Professor Trapani added.
The UK team was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust.
Image: Model of a membrane with perforin rings allowing the passage of granzymes into the cell. Credit: Mike Kuiper
Reference
Law R et al. The structural basis for membrane binding and pore formation by lymphocyte perforin. Nature 2010.
