Researchers from Greifswald and KU Leuven (Belgium) have for the first time decoded in detail how an important blood enzyme—ADAMTS13—is structurally regulated. This enzyme acts as a kind of "safety mechanism": it prevents the formation of dangerous blood clots that can block small vessels.
A long-unsolved mystery
The study provides the most precise model to date of how ADAMTS13 switches between its inactive and active states. "It was known in the field that ADAMTS13 exists in a closed state," explains first author Norman Geist of the University of Greifswald. "But we didn't understand the structural logic behind it. The results are very important because they finally provide a clear blueprint for a puzzle researchers have been trying to solve for over 20 years." At the heart of the discovery is a previously underestimated component of the enzyme: a flexible connecting region known as the "L3 linker." The researchers were able to show that this region acts like a built-in protective cap. It blocks important binding sites and thereby keeps the enzyme inactive—until it is actually needed. In doing so, it mimics the actual substrate VWF-A2 through similarity in amino acid sequence. The principle can be illustrated like a zipper: different parts of the enzyme "interlock" with one another and stabilize the closed state. When ADAMTS13 is needed, this structure can quickly reopen.
Simulation meets experiment
To visualize this complex mechanism, the researchers combined elaborate computer simulations with experimental laboratory work. They used an algorithm developed in Greifswald that can calculate the movements of biomolecules with particular efficiency and precision. The simulations themselves ran for several years on specialized high-performance computers in Göttingen, as exceptional computing power was required. "This work shows how advanced computational modeling and experimental thrombosis research can now be combined at an unprecedented level," says Dr. Mihaela Delcea, Professor of Biophysical Chemistry at the University of Greifswald. The findings not only help improve our understanding of fundamental processes in the human body. In the long term, they could also provide new approaches for treating serious diseases. These include the rare but life-threatening condition thrombotic thrombocytopenic purpura (TTP), in which the regulation of ADAMTS13 is disrupted.
Perspectives for new therapies
"If we know exactly where this molecular zipper is located, we will be able to develop significantly more precise therapies in the future," says Norman Geist. "In the long run, this could enable the development of molecules that can return ADAMTS13 to its closed state or stabilize it there in cases of dysregulation."
Source: Presse Release Universität Greifswald
Original publication: Geist N, Bonnez Q, Vanhoorelbeke K, Delcea M. Wrapping it Up: Structural Basis of ADAMTS13 Global Latency. bioRxiv; 2025. DOI: 10.1101/2025.11.26.689657
