Targeted protein degradation – from small molecules to complex organelles

• Applicant: Professorin Dr. Petra Beli
• Subject Area: Biochemistry
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 433961759

The targeted degradation of proteins is essential for cellular function and fitness of the organism. Damaged proteins must be recognized and removed to prevent collateral damage, while numerous signaling pathways rely on the specific degradation of proteins. Two major pathways for protein degradation in eukaryotic cells are the ubiquitin-proteasome system (UPS) and autophagy. Perturbations in the UPS and autophagy cause severe pathological conditions including cancer and neurodegeneration. In the UPS the substrates are tagged with ubiquitin, which targets them to the proteasome where they are unfolded and degraded. In contrast, autophagy is a degradation pathway that delivers the substrates for proteolysis into the lysosome. This is achieved by encapsulating them within double membrane vesicles, which subsequently fuse with lysosomes. Proteinaceous substrates targeted by autophagy are also marked with ubiquitin.In this SFB, we will address the molecular mechanisms of how proteins destined for degradation are channeled between the UPS and autophagy focusing on protein degradation in the cytoplasm and nucleus. In addition to addressing the crosstalk between the two major proteolytic pathways, we will investigate how small molecules can be used to chemically reprogram the distinct degradation systems, enabling the targeted proteolysis of selected proteins in a spatially and temporally controlled manner. In fact, the latter method has huge potential in medical research, leading to the development of novel anti-cancer drugs, for example. To reach the ambitious aims outlined above, we have assembled an exceptional team combining expertise in UPS and autophagy as well as utilizing a complementary set of methods including structural biology, protein chemistry, chemical biology, biochemistry, mass spectrometry, cell biology and molecular medicine.

• DFG Programme: Research Grants
• International Connection: Austria