GRK 2606:  Understanding protease functions in cellular pathways through discovery and analysis of protease substrates (ProtPath)

• Subject Area: Basic Research in Biology and Medicine
• Term: since 2021
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 423813989

Proteases play crucial roles in nearly all biological processes, driving essential functions through degradative proteolysis or by generating cleavage products with new functionalities or specific subcellular locations. Given the mostly irreversible nature of proteolysis, protease activity is tightly regulated, including through expression control, localization, or zymogen maturation. During GRK 2606's initial funding period, many projects highlighted that proteolysis is also regulated by diverse protein-protease interactions and have proteolysis-independent biological functions. With around 460 enzymes in humans, proteases are physiologically significant, and since most protein substrates are targeted by multiple proteases, each producing distinct outcomes, cellular proteolysis forms a complex network. Dysregulation of proteases underpins many diseases, such as cancer and neurodegenerative disorders, making them key therapeutic targets. Despite this, many proteases have few identified substrates or interactors, highlighting the still-emerging complexity of cellular proteases as regulatory switches. Upon renewal the research program of GRK 2606 will address key research areas, including protease substrate identification, molecular interactions regulating proteases, protease specificity, non-catalytic interactions of proteases, and the physiological and pathological consequences of protease activity. Therefore, GRK 2606 explores various protease families, integrates omics methodologies with biochemical and cell-biological approaches, and has outreach to clinical translation. This interdisciplinary effort necessitates collaboration among well-trained PhDs and MDs to advance protease research and develop novel protease-based diagnostics and therapies. To meet this challenge, we developed a comprehensive research training program that integrates international doctoral students from natural and clinical sciences, guided by Principal Investigators with comprehensive expertise in the relevant research areas and training of doctoral researchers. Our program transforms doctoral candidates into postdoctoral scientists with deep protease research expertise, preparing them for successful careers in academia, medicine, or industry. The training emphasizes multidisciplinary skills, international exchange, communication, and ethical as well as lawful science conduct, equipping trainees to lead in their fields and contribute meaningfully to science and society.

• DFG Programme: Research Training Groups
• Applicant Institution: Albert-Ludwigs-Universität Freiburg
• Spokesperson: Professor Dr. Thomas Reinheckel
• Participating Researchers: Professor Dr. Matthias Eder; Dr. Ruth Geiss-Friedlander; Professor Dr. Olaf Groß; Professor Dr. Pitter Huesgen; Professor Dr. Georg Häcker; Privatdozent Dr. Klaus-Peter Knobeloch; Professorin Dr. Claudine Kraft; Professorin Dr. Diana Lindner; Privatdozent Dr. Ulrich Maurer; Professor Dr. Chris Meisinger; Professor Dr. Oliver Schilling