For the first time, scientists at University of Leeds reveal a complex mechanism behind blood clotting.
The findings, published in Science Advances , visualise a key component of blood clotting - platelet myosin – and how it is activated.
Using the powerful cryo-EM technology imaging equipment housed in the University's Astbury Biostructure Laboratory, scientists found key regions of the myosin which are responsible for keeping it inactive. In doing so, they also revealed hotspots for inherited disease mutations, such as bleeding disorders. Mutations in this type of myosin also cause deafness and kidney disorders.
Professor Michelle Peckham, from the University's School of Molecular and Cellular Biology, said: "By understanding how this molecule is normally kept under control, we can begin to see how genetic mutations push it out of balance and lead to disease."
Myosins are motor proteins that carry out a wide range of jobs, such as driving the contraction of muscles and beating of the heart.
Humans have lots of different types of myosins, all exquisitely adapted for specific functions in cells.
The type of myosin investigated in this new study, platelet myosin, is important in non-muscle cells, like special cells called platelets – blood cell fragments which are critical for blood clotting.
When blood clots (i.e. to stop the body from bleeding), platelets rush to the injury and stick together to plug the hole.
Inside each platelet is a kind of internal "scaffolding" called the cytoskeleton which enables them to attach and form the clot.
Up until now, scientists knew that this internal scaffolding and platelet myosin works with a molecule called actin to actively pull on and compact a network of fibres which causes the seal.
But a critical question remained - how does the platelet myosin keep itself inactive until it is needed?
Glenn Carrington, postdoctoral researcher at the Astbury Centre for Structural Molecular Biology, said: "What's exciting is that we can now explain, in structural detail, how this molecule folds in on itself to stay inactive—and how a simple chemical change flips it back on."
In visualising the structure of platelet myosin, interdisciplinary researchers based at the Astbury Centre for Structural Molecular Biology also showed how key regions of the molecule critical for keeping the molecule switched off are also hotspots for inherited mutations.
These mutations are likely to destabilise the shutdown myosin, so it becomes prematurely activated, disrupting normal platelet function.
This lack of regulation will reduce the ability of the platelets to assemble their cytoskeleton properly when needed, and reduce their ability to form clots - leading to bleeding disorders.
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