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Biological Sciences researchers capture the immune system's killer weapon red-handed

Collaborative research determines the structure of the protein perforin which will help scientists design drugs to enhance or prevent its activity.

Composite image shows: (left) killer cell in act of killing virus infected cell using perforin to punch a hole in the cell membrane; (right) two views of a ring of perforin molecules. (Source: research team)

Researchers in the Department of Biological Sciences at Birkbeck, in collaboration with a group at the Peter MacCallum Cancer Centre in Melbourne, have determined the structure of a protein assembly used by the immune system to kill unwanted cells. The protein perforin sits within these killer cells and its role in human health is finally balanced. The unfortunate individuals who lack functional perforin usually die of infection or cancer in early childhood, but overactive killer cells can trigger inflammation and kill healthy cells resulting in serious organ damage.

Marina Ivanova, former postdoctoral researcher in the Department and now at Imperial College, determined the perforin structure when she worked in Professor Helen Saibil's group and the research paper has been published in Science Advances. Understanding the details of perforin pore structure will help scientists design drugs to enhance or prevent its activity, eventually leading to new therapeutics to treat certain autoimmune diseases and the condition familial hemophagocytic lymphohistiocytosis.

How perforin works

When the immune system detects virally infectious or cancerous cells it uses cytotoxic T lymphocytes and natural killer cells to destroy them. Within these cytotoxic and killer cells there are small membrane parcels filled with the protein perforin, which can punch holes through cell membranes, along with the toxic granzyme enzymes. When an infected cell is detected, the killer cell latches onto it and ejects some of the toxic membrane parcels allowing the perforin protein to punch holes in the target cell membrane, through which the toxic granzymes enter, causing the target cell to rapidly die (as shown in the left hand image above), and then moving on to deal with the next infected cell in quick succession.

The structure of perforin

Perforin is made as single protein molecules that are stored inside their membrane compartment until they are needed, but when they are released, they join up into rings of around 22 molecules and undergo a dramatic shape change in order to punch the hole through the target membrane. Two views of the pore structure are shown in the right hand panel of the image.

Further Information

Article: The pore conformation of lymphocyte perforin

Research in the Department of Biological Sciences


Peter MacCallum Cancer Centre, Melbourne

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