We proudly announce the Awardee of the "Frischauf-Award 2013": Elfriede DALL.
"Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation"
Elfriede Dall and Hans Brandstetter
The cysteine protease legumain plays important functions in immunity and cancer at different cellular locations, some of which appeared conflicting with its proteolytic activity and stability. Here we report crystal structures of legumain in the zymogenic and fully activated form in complex with different substrate-analogues. We show that the eponymous Asparagine-specific EndoPeptidase activity (AEP) is electrostatically generated by pH-shift. Completely unexpectedly, the structure points towards a hidden carboxypeptidase activity that develops upon proteolytic activation with the release of an activation peptide. These activation routes reconcile the enigmatic pH-stability of legumain, e.g. lysosomal, nuclear and extracellular activities in immunology and cancer. A dual pH dependence tightly regulates substrate access and turnover by selective protonation of the S1 pocket (KM) and the catalytic nucleophile (kcat), respectively. The multi-branched and context-dependent activation process of legumain illustrates how proteases can act not only as signal transducers but also as decision makers.
Reference: Dall E & Brandstetter H (2013) Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation. Proceedings of the National Academy of Sciences of the United States of America 110(27):10940-10945.
The open access article can be found here