Photo by Richard Ling
Research involving the stonefish—an animal that protects itself using razor-sharp, venom-filled spines—has provided unexpected insight into the human immune response that causes hematopoietic stem cell transplants (HSCTs) to fail.
The insight is now being used to develop immunosuppressants that could potentially improve the success rate of HSCTs.
Researchers explained this surprising connection in PNAS.
Their study indicated that the lethal component of stonefish venom, a protein called stonustoxin, is an ancient relative of the human immune protein perforin.
The body unleashes perforin to destroy virally infected and cancerous cells. Unwanted or excessive perforin activity is responsible for a range of medical problems, including the rejection of HSCTs.
Perforin proteins attach themselves to a cell and assemble to form giant 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 current study has revealed a key part of the pore-assembly mechanism.
To make this discovery, the researchers used synchrotron radiation to visualize the atomic structure of stonustoxin. They found the toxin contains 2 perforin-like proteins stuck together.
Seeing how these 2 proteins interact has helped the researchers on their way to understanding how the full assembly of 20 perforin molecules forms a complete pore.
The team is also using their new insight 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,” said James Whisstock, PhD, of Monash University in Melbourne, Victoria, Australia.
“This type of mechanistic information is extremely useful in developing new strategies to inhibit perforin itself.”
