Work

Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation

Year: 2013

Type: article

Abstract: 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 analogs. We show that the eponymous asparagine-specific endopeptidase activity is electrostatically generated by pH shift. Completely unexpectedly, the structure points toward 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 with relevance in immunology and cancer. Substrate access and turnover is controlled by selective protonation of the S1 pocket (KM) and the catalytic nucleophile (kcat), respectively. The multibranched and context-dependent activation process of legumain illustrates how proteases can act not only as signal transducers but as decision makers.

Source: Proceedings of the National Academy of Sciences

DOI: 10.1073/pnas.1300686110

Authors: Elfriede Dall, Hans Brandstetter

Institution: University of Salzburg

Language: English

Topic: Protease and Inhibitor Mechanisms

Subfield: Cancer Research

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: green

Estimated APC paid: $1,003

Funders: European Synchrotron Radiation Facility, Austrian Science Fund