Everyone is familiar with the pain of skinned knees. However, the complex pathway of proteins that works behind the scenes after the bleeding has stopped is not as well known. Central to this process is the production of plasmin, a powerful blood enzyme that disposes of blot clots. Doctors also harness the "clot busting" abilities of plasmin to treat patients who suffer heart attack or stroke. Now, a study published by Cell Press on March 8th in the journal Cell Reports provides remarkable new insight into how plasmin is produced. This work may lead to more effective clot-busting drugs.
Plasmin is released into the blood in an inactive form called plasminogen. Circulating plasminogen is curled up in a "closed," activation-resistant form. In order for plasminogen to be converted to plasmin, it must first undergo a dramatic change in shape and "open" itself up. "We know that activation of plasminogen is tightly regulated," explains senior study author, Prof. James Whisstock, from Monash University in Melbourne, Australia. "However, without knowing the atomic details of the closed form of plasminogen, it is impossible to understand what causes it to change shape and how it is converted to plasmin by plasminogen activators."
Researchers from Monash University and the Australian Synchrotron have now solved the long-sought-after atomic structure of closed plasminogen. "We were very surprised to find that a simple sugar tethered to plasminogen guards access to the site of activation," says Dr. Tom Caradoc-Davies, from the Australian Synchrotron. Most remarkably, however, the researchers also found that plasminogen plays a kind of peek-a-boo with the blood clot. "We found one part of plasminogen seems to be very unstable and transiently opens up a tiny bit. Proteins in the blood clot bind to this 'Achilles' heel' when it is exposed, trapping plasminogen in the open form that can be activated," says lead author, Dr. Ruby Law, from Monash University.
"We use plasminogen-activating drugs to treat stroke and other life-threatening disorders associated with blood clots. However, until now, the molecular details for these therapeutic effects have never been understood," concludes co-senior author, Paul Coughlin, a clinical hematologist from the Australian Centre for Blood diseases. "Now, with the structure of plasminogen and an enhanced understanding of how it is converted to plasmin, we finally have a platform to develop new and more effective clot-busting therapeutics."