Crystal structures of human legumain unveil activation mechanisms to distinct peptidase activities

Structure and regulation of (pro-)legumain. The catalytic Cys189 is indicated in sticks representation. Top-view on the AEP active site shows how Glu190 stabilizes the protonated state of Cys189 Sg.
Dall E. et al., Proc Natl Acad Sci USA 110, 27 (2013)
The cysteine protease legumain is a key player in immunity and cancer at different cellular locations, some of which are incompatible with its pH-stability. We solved the crystal structures of zymogenic and active legumain, unveiling its activation and regulation principles. Legumain contains an Asn-specific endopeptidase activity that is electrostatically released at acidic pH. Surprisingly, we uncovered a complementary proteolytic activation route, generating a carboxypeptidase activity. The context-dependent activation of legumain reconciles its partly conflicting moonlighting activities.

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Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation; Dall E. and Brandstetter H., Proc Natl Acad Sci USA 110, 27 (2013); doi:10.1073/pnas.1300686110

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