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J Biol Chem. 2011 Dec 23;286(51):43726-34. doi: 10.1074/jbc.M111.291310. Epub 2011 Oct 25.

The plasticity of the β-trefoil fold constitutes an evolutionary platform for protease inhibition.

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Protein Chemistry Unit, Faculty of Medicine, Université Libre de Bruxelles, Campus Erasme (CP 609), 808 Route de Lennik, B-1070 Brussels, Belgium.


Proteases carry out a number of crucial functions inside and outside the cell. To protect the cells against the potentially lethal activities of these enzymes, specific inhibitors are produced to tightly regulate the protease activity. Independent reports suggest that the Kunitz-soybean trypsin inhibitor (STI) family has the potential to inhibit proteases with different specificities. In this study, we use a combination of biophysical methods to define the structural basis of the interaction of papaya protease inhibitor (PPI) with serine proteases. We show that PPI is a multiple-headed inhibitor; a single PPI molecule can bind two trypsin units at the same time. Based on sequence and structural analysis, we hypothesize that the inherent plasticity of the β-trefoil fold is paramount in the functional evolution of this family toward multiple protease inhibition.

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