We now have a much clearer idea of how our body's immune system kills cancer cells and cells infected with viruses, thanks to a joint UK and Australian project.
Researchers from Monash University, the Peter MacCallum Cancer Institute in Melbourne, and Birkbeck College in London, collaborated to unravel the structure of the protein called perforin and determine how it works to kill rogue cancer cells and normal cells that have been infected with pathogens such as viruses.
Their research was published today in the journal Nature.
The existence of perforin was discovered in the 1980s, but until now, its structure and mechanism of action have remained a mystery, says Professor James Whisstock from Monash University, an ARC Federation Fellow, and one of the authors of the Nature paper.
Both teams of researchers owe their findings to recent advances in crystallographic techniques.
The Melbourne researchers used the Australian Synchrotron — a large, circular particle accelerator — to fire x-rays at perforin crystals. They then measured the diffraction of the x-rays caused by the atoms of perforin to determine its structure.
Meanwhile, the London researchers used another crystallography technique, cryo-electron microscopy, to look at how the perforin molecules form a pore on the surface of a membrane.
Both teams' results were combined to give a picture of how perforin functions.
"What we found was that perforin is a long, thin, very flat molecule shaped like a key," says Professor Whisstock.
"The rounded part of the key, which looks like the bit of a key you hold with your fingers, penetrates the cell membrane, while the long part of the molecule, the part of the key that would go into a lock, attaches to other perforin molecules," he says.
The perforin molecules then arrange themselves into a circle and form a pore on the membrane surface, which acts as an opening through which cytotoxic molecules from the T cells can enter the target cells and destroy them.
They also found that the structure of perforin is very similar to that of the toxins produced by some pathogenic bacteria such as streptococcus and anthrax. These bacteria use much the same mechanism of action to attack the cells of their hosts.
Professor Whisstock says the discovery has important clinical implications.
For example, there is a rare inherited condition called familial haemophagocytic lymphohistiocytosis, in which a person is born without the ability to make perforin, he says.
This condition causes the person to suffer frequent bouts of fever and infection. Without treatments such as a bone marrow transplant, the condition is usually fatal.
Knowing how perforin works may lead to better treatments, he says.
Perforin is also thought to be involved in the cause of many of the so-called 'autoimmune diseases' such as Type 1 diabetes, in which the body's T cells wrongly attack healthy normal tissue.
Researchers from the Peter MacCallum Cancer Institute are now working on drugs that inhibit the action of perforin, and may one day lead to better treatments for these conditions.