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Breakthrough in exploration of protein dynamics

Using a uniquely informative technology, a team of Danish researchers has discovered a new type of peptide chain dynamics that controls the stability of the PAI-1 protein. The discovery provides a better basis in the long term for intervening in diseases associated with increased risk of blood clots.

2014.07.30 | Lisbeth Heilesen

The changes in the red and blue bands show the recently discovered local unfolding of PAI-1 just before it is inactivated. Also shown is how the green parts of proteins are rearranged in connection with the inactivation. Figure: Morten Beck Trelle and Peter A. Andreasen

Proteins are normally expected to have a stable three-dimensional structure with a well-defined fold of the peptide chain. However, there is much to indicate that the protein peptide chains constantly undergo small movements at widely varying rates.

In the case of PAI-1, such movements now appear to be crucially important for a molecular inactivation process that is closely connected to its biological function. In contrast to most other proteins, the folding of PAI-1 is actually unstable, which means that it is spontaneously inactivated within a couple of hours by one of the largest known conformational changes of a folded protein. This conformational change is in fact due to a special type of dynamics in the PAI-1 peptide chain, in the form of local transient unfoldings lasting several minutes.


This is the message in an article ("hot paper") just published in the highly reputed chemistry journal Angewandte Chemie. The discovery was made using a special technique called HDX-MS (hydrogen-deuterium exchange monitored by mass spectrometry), and the world’s leading experts in this technique are Morten Beck Trelle and Thomas J. D. Jørgensen, University of Southern Denmark (USD). The investigations leading to the new results were only made possible by the unique instrumentation at the Department of Biochemistry and Molecular Biology at USD. The USD researchers collaborated with the PAI-1 experts Jeppe Buur Madsen and Peter A. Andreasen, Department of Molecular Biology and Genetics, Aarhus University (AU).

The results were achieved as part of a western Danish project headed by Peter A. Andreasen, with finance amounting to DKK 14.1 million provided by the Danish Council for Independent Research | Technology and Production Sciences. The project has already resulted in a number of biochemistry and structural biology publications, but the article in Angewandte Chemie represents the scientific high point to date.

Forskerne bag de nye resultater i Angewandte Chemie

The researchers behind the new results in Angewandte Chemie.


Better basis for intervention in diseases associated with increased risk of blood clots

The scientific perspective of the discovery is a much better basic understanding of the structural dynamics of proteins, while the discovery also provides a better basis for intervention where there is a risk of blood clots. PAI-1 stands for plasminogen activator inhibitor 1, and PAI-1 is a rapid and specific inhibitor of two enzymes – plasminogen activators – found in blood and surrounding the cells in the organism. The two enzymes are mostly known for their ability to dissolve blood clots, both naturally and pathologically in wounds and thrombi, respectively. In accordance with this, PAI-1 deficiency is connected with a risk of bleeding. However, PAI-1 is best known in connection with conditions such as type 2 diabetes, where blood levels that are too high are connected with an increased risk of blood clots. PAI-1’s built-in inactivation function probably developed by evolution as a protection against the risk of blood clots.

The new discovery provides a much better basis for pharmacologically adjusting the speed at which the decay process takes place, which in the long run provides a better basis for intervention in diseases connected with an increased risk of blood clots.


Link to the scientific article in Angewandte Chemie: Local transient unfolding of native state PAI-1 is associated with Serpin metastability.


More information

Professor Peter A. Andreasen
Department of Molecular Biology and Genetics
Aarhus University, Denmark
pa@mb.au.dk – mobile: +45 2899 2589

Research