The protein von Willebrand factor circulates in the blood. In response to wounds, this protein causes platelets to stick together, which limits blood loss by sealing damaged blood vessels. Last year it was found that the action of this protein is dependent on the force of blood flow. This force increases when blood vessels are damaged or when they become blocked by excessive blood coagulation. The research groups headed by Eric Huizinga (Utrecht University) and Sander Tans (FOM institute AMOLF) have now shown how this mechanism works at the molecular level.
Using detailed 3D recordings, the Utrecht researchers were able to detect the calcium atom that controls the protein’s effect on blood coagulation. "By shining X-rays through crystallized von Willebrand factor, we can see details of the protein’s structure at the atomic level" comments Arjen Jakobi of Utrecht University. "This enabled us to accurately determine how calcium causes the protein to adopt a compact folded structure in response to a blood flow that exerts little force."
The manipulation of single von Willebrand factor proteins then showed how the protein responds to an increased force. Sander Tans of the FOM Institute AMOLF: "Using laser beams we created a 'molecular tweezers', which allowed us to pull on the ends of the protein. We could thus measure the force required to unravel the normal compact structure of the protein, causing its function to change."
The researchers also discovered how, when damaged blood vessels have been repaired, the calcium helps to stop blood coagulation and thus prevent thrombosis. When a blood vessel becomes almost completely blocked by platelets, there is a risk of thrombosis. Under such conditions, the sheer force of blood flow causes von Willebrand factor to unravel, exposing it to partial breakdown by enzymes. Von Willebrand factor that has been partially broken down in this way bonds to platelets less actively, thereby preventing thrombosis.
However, excessive breakdown could lead to bleeding. A single calcium atom can prevent this by acting as a sort of protein glue, which causes the von Willebrand factor to fold up again as the force decreases. According to Eric Huizinga of Utrecht University, "Calcium gives the von Willebrand factor the unique ability to respond like a tiny switch to the force of blood flow. This allows the protein to stop any bleeding quickly, while reducing the risk of thrombosis to a minimum."
This research was funded by NWO.
"Calcium modulates force sensing by the von Willebrand factor A2 domain",
Arjen J. Jakobi, Alireza Mashaghi, Sander J. Tans & Eric G. Huizinga
Nature Communications DOI 10.1038/nacomms1385