Proteases as Master Switches in Cancer

Biological signaling represents a highly complex decision matrix that must be reflected by the activity regulation of proteases, universal master switchers in health, and disease. The cysteine protease legumain exemplifies how intricate multifactorial processes combine in zymogen activation and activity regulation. These principles are key to accomplish its demonstrated roles in (auto-)immunity and cancer.

 

The Brandstetter lab has recently succeeded in the determination of legumain architecture which revealed completely unexpected enzymatic functions and mechanisms. In total, legumain harbors three distinct enzymatic functions. These orthogonal functions are accomplished by pH-dependent activation pathways and by capitalizing on the specific molecular properties of the substrate molecule itself, a process described as substrate-assisted catalysis. These principles enable legumain to exploit endopeptidase and carboxypeptidase activities at acidic and neutral pH, respectively. Thereby, legumain cleaves a substrate into two peptides in a reaction that is said to be irreversible. Defying the dogma of an irreversible cleavage reaction, legumain is also able to act as peptide ligase on certain substrates. These activities are steered by subtle changes of the cellular environment, such as pH or location. This increase understanding is hoped to pave the way for improved diagnosis in cancer patients. 

 

Visit Brandstetter lab at PLUS

 

Selected publications

 

  • Dall E, Brandstetter H. 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 2013;110:10940-5. IF: 9.8

  • Eckhard U, Schonauer E, Nuss D, Brandstetter H. Structure of collagenase G reveals a chew-and-digest mechanism of bacterial collagenolysis. Nature structural & molecular biology 2011;18:1109-14. IF: 11.6

Hans Brandstetter, PhD

Professor for Structural Biology

Department of Biosciences

University of Salzburg

hans.brandstetter@sbg.ac.at

Proteases in Cancer

Proteases in Cancer and Immunity

The immune system recognizes both external invaders (bacteria and viruses) and internal aberrations (tumours). To this end, each cell has to identify itself towards the immune system by presenting intracellular peptides at the cell surface. Despite its enormous efficiency, some harmful cells escape the screening (pass control) of the immune system by presenting unsuspicious peptides only. We investigate the complex protease machinery involved in peptide processing. A detailed understanding promises treatment options against tumours.

Cancer Cluster Salzburg at SCRI

3rd Medical Department

Paracelsus Medical University Clinics Salzburg

Müllner Hauptstrasse 48, 5020 Salzburg, Austria

Email: ccs@sbg.ac.at

Cancer Cluster Salzburg at PLUS

Department of Biosciences

University of Salzburg

Hellbrunner Strasse 34, 5020 Salzburg, Austria

Email: ccs@sbg.ac.at