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Mechanistic and structural studies on legumain explain its zymogenicity, distinct activation pathways, and regulation.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Jul 02; Vol. 110 (27), pp. 10940-5. Date of Electronic Publication: 2013 Jun 17. - Publication Year :
- 2013
-
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.
- Subjects :
- Amino Acid Sequence
Catalytic Domain genetics
Crystallography, X-Ray
Cysteine Endopeptidases genetics
Enzyme Activation genetics
Enzyme Precursors chemistry
Enzyme Precursors genetics
Enzyme Precursors metabolism
Enzyme Stability genetics
Humans
Hydrogen-Ion Concentration
Kinetics
Models, Molecular
Molecular Sequence Data
Protein Conformation
Sequence Homology, Amino Acid
Signal Transduction genetics
Cysteine Endopeptidases chemistry
Cysteine Endopeptidases physiology
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23776206
- Full Text :
- https://doi.org/10.1073/pnas.1300686110