Synchrotron solves clot-busting enzyme riddle

It took some of the most powerful X-rays that the Australian Synchrotron can generate, but researchers have now solved a century old puzzle of how a clot-busting enzyme, plasminogen, is activated in the body.

The finding, published today in Cell Reports, is hoped to lead to new treatments for clotting and bleeding disorders as well as certain types of cancer.

The researchers, led by Professor James Whisstock and Associate Professor Paul Coughlin, along with colleagues at the Australian Synchrotron, used the X-ray beamline to reveal the atomic structure of plasminogen to reckon how it’s converted into plasmin, an enzyme that removes disease-causing clots and clears up damaged tissue.

According to Whisstock, from the School of Biochemistry and Molecular Biology at Monash University, scientists have been trying for nearly a century to understand how plasminogen is activated to plasmin.

“Now we can see the atomic details of the plasminogen we can finally get a detailed picture of how the whole system works and how plasmin is produced,” he said.

Co-lead author, Dr Ruby Law, also of Monash University, said plasminogen displayed unexpected behaviour.

“A casual look at the structure would suggest that plasminogen seems to completely guard its activation site. However, we found that one part of plasminogen seems to be very unstable and can transiently pop open a fraction – a little like a child playing a game of ‘Peek-a-boo’,” she said.

“Proteins in the blood clot bind to this part of the molecule when it is exposed, with the result that plasminogen is trapped in a form that can be converted to plasmin.”

Dr Tom Caradoc-Davies, Principal Scientist on the Macromolecular Crystallography beamline, said the results came after months of collaboration between Monash University Researchers and the Australian Synchrotron science group.

“We strongly believe these findings will lead to the design of better anti-blood clotting drugs and drugs to actively treat bleeding disorders and certain cancers,” he said.

Clinicians currently use drugs called plasminogen activators to generate plasmin in treating heart attack and stroke patients. Also, as plasmin is responsible for breaking down tissue barriers in cancer, a large number of researchers worldwide are developing plasmin inhibitors as anti-cancer therapeutics.

“In the past, the molecular details of plasminogen-activating drugs used to treat strokes were not entirely understood,” said Whisstock. “This latest discovery by Monash and the AS science team means drug companies will now be able to fine tune their development of next generation anti clotting/‘clot busting’ drugs and cancer treatments.”