The stonefish is one of the world’s ugliest and deadliest fish. You’ll know if you step on one; the fish protects itself using 13 razor sharp venom filled spines capable of slicing through reef shoes. The resulting pain is crippling, can last for days and may result in amputation of a limb or death.
Structural Insights of the Stonefish toxin may help combat Transplant Rejection, ie the unexpected insight into a crucial human immune response that is responsible for the failure of up to 30% of bone marrow transplant therapies for treating leukaemia. The knowledge has been used to develop immunosuppressants to improve the success rate of transplant therapies.
The work reveals that the lethal component, a protein, Stonustoxin, is an ancient relative of the human immune protein perforin. In humans, perforin is an essential weapon unleashed to destroy virally infected and cancerous cells. Perforin proteins attach themselves to a diseased cell and assemble to form giant ring shaped holes, or pores, on the cell surface. Each pore contains around 20 perforin proteins that stick together in a symmetrical fashion. The pores are big enough to allow toxins to enter the cell, killing it from within. How these pores form is a mystery but the work on stonustoxin has revealed a key part of the pore assembly mechanism.
To make their discovery, the team used powerful synchrotron radiation to visualise the atomic structure of stonustoxin. Crucially, they found that the toxin contains 2 perforin-like proteins stuck together. By seeing how two of the proteins first interact, the researchers can build on this to understand how the full assembly of 20 perforin molecules forms a complete pore.
“The lethal factor in stonefish venom is like a loaded gun – ready to fire as soon as it is injected into the foot of an unsuspecting victim,” co-lead author Dr Sheena McGowan said. In humans, unwanted or excessive perforin activity is responsible for a range of medical problems including pancreatic cell destruction in type I diabetes and the rejection of bone marrow transplants in the treatment of leukaemia.
An international group of researchers, led by the Peter MacCallum Cancer Institute and including Monash based Professor Whisstock and his team, are working to develop perforin inhibitors. “Already the structure of stonustoxin is starting to inform our drug development program, and we now understand the very first stages of perforin pore formation. This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself,” co-lead author Professor Whisstock said.
“People who step on a stonefish suffer agonising pain because the lethal stonustoxin protein attacks nerves. The treatment for envenomation includes an anti-venom together with soaking the wound in non-scolding hot water – the latter treatment unravels the venom and stops it punching holes,” he said. http://www.monash.edu/news/show/deadly-blessing-studying-stonefish-venom-may-help-combat-transplant-rejection
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