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29-Sep-2019

Enzyme’s ‘molecular scissors’ cut out fatal blood clot risk

New research highlights how an essential enzyme works to prevent dangerous clots 

By stopping bleeding and allowing wounds to heal, our blood’s ability to clot is a vital part of how the body rebuilds and recovers following an injury. In many diseases clots can continue to grow and prevent blood from flowing properly, leading to serious diseases.

In a new study in Nature Communications, researchers from Imperial College Londonthe University of Nottinghamand KU Leuven have revealed fresh insights as to why this important biological process can sometimes go awry in a study funded by the Medical Research Council and British Heart Foundation. 

The findings show how a crucial enzyme in our blood, known as ADAMTS13, works like a pair of molecular scissors to carefully cut back the clotting effects of a key protein, von Willebrand factor (VWF). By resolving the crystal structure of the functional domains of ADAMTS13, the research reveals how after binding VWF, the enzyme must change its shape to open the active site and in turn specifically accommodate the cleavage site in VWF.  

Cutting clot risk

When blood vessels are damaged by a cut or by other types of vascular injury, VWF in blood plasma binds to the site of damage and unravels to form long protein strings that specifically capture specialised blood cells (platelets) to the site of injury. This serves to stem the flow of blood and reduce bleeding. If VWF is deficient, patients bleed. Conversely, if VWF is not regulated properly by ADAMTS13, it can result in thrombotic events such as heart attack, stroke or the life-threatening blood disorder thrombotic thrombocytopenic purpura (TTP). This is because when VWF is produced, it is hypersensitive to blood flow. Therefore, if VWF function is not adequately controlled this leads to excessive platelet clumping and clot formation. 

While previous research demonstrated the important role of ADAMTS13 in regulating VWF, the findings published in Nature Communicationspinpoint the specific molecular mechanisms underlying this crucial relationship between enzyme and substrate. Based on the study team’s exploration of the enzyme’s crystal structure, we now know that ADAMTS13’s unique butterfly-like shape allows it to bind specifically to VWF when it recognises the protein in our blood. Once bound, the enzyme acts as a pair of molecular scissors, trimming down VWF’s sticky protein strings and thereby preventing it from amassing blood cells excessively into a dangerous clot. Once ADAMTS13 has tailored the clotting effects of the VWF, it reverts into a latent form which stops it from degrading other important proteins in our body. In this form, the enzyme also becomes resistant to inhibitors, allowing it to exist in our blood for longer.

‘Feel the Force’ of blood movement

VWF forms long protein strings which act like velcro and recognise areas of the blood vessels that need repairing. VWF has the remarkable property that it folds up into an inactive form, but it is able to ‘feel the force’ of the blood moving around it and in so doing alter its shape which changes it into an adhesive protein capable of capturing blood platelets, leading to it being described as the ‘Jedi Knight’ of the blood stream (quote from professor Timothy Springer, Harvard University). 

The new study has revealed the butterfly shape of this molecular scissor that cleaves the VWF strings down to size and enzyme activation is driven by force induced sensing and unfolding of VWF which is able to unpick the lock of the latent form of the ADAMTS13 enzyme active site through a mechanism that remains to be discovered.

New treatments for blood disorders

The study team are now keen to explore how this new knowledge of ADAMTS13’s highly-specialised structure can be used to develop treatments for strokes, heart attacks and rare blood disorders.

Professor Jonas Emsley, School of Pharmacy at the University of Nottingham commented: “As the ADAMTS13 has a critical role in shaping VWF and guiding its sensitivity to force, ADAMTS13 may be viewed as the ‘Jedi master' enzyme of the blood. The pharmaceutical industry will benefit from this research through the potential to rationally modify and develop ADAMTS13 as a therapeutic agent. To do this, it is essential to understand its structure and function. To know which parts of the molecule are important (or redundant), and what the limiting steps in its production and function are central to facilitating this and design means to avoid recognition by the immune system,” 

Professor James Crawley(Department of Immunology and Inflammation from Imperial College London commented: “The results from our study provide a remarkable insight into how the body specifically controls blood clotting. The mechanisms that we have uncovered beautifully exemplify how evolution has come up with elegant solutions to regulate complex biological systems. ADAMTS13 is one member of a family of enzymes, that all likely share a common mode of action. ADAMTS13 is the best-characterised member of this family. Therefore, our data not only provide important insights into human thrombotic diseases and potential novel therapeutics but also inform how the other ADAMTS family members may behave in many different and diverse biological systems.”

Professor Karen Vanhoorelbeke (KU Leuven) added: “Our study highlights the importance of combining expertise from different international research groups to realize scientific breakthroughs. Joining forces in determining crystal structures of proteins, enzyme kinetics and monoclonal antibody development allowed us to reveal how our body specifically controls this part of the blood clotting.”

“The pharmaceutical industry is currently running trials of recombinant ADAMTS13 in the setting of thrombotic thrombocytopenic purpura (TTP). Work from this proposal will provide a molecular structure of ADAMTS13 in isolation and in complex with its substrate. Importantly, this will provide the opportunity to improve the ADAMTS13 molecule through targeted modification to reduce immunogenicity in inherited TTP, reduce inhibition and clearance in acquired TTP, and to reduce ADAMTS13 clearance and so prolong plasma half-life (improving bioavailability, reducing dosing/frequency of dosing).”

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Last Updated: 30-Sep-2019