SFB 969:  Chemical and Biological Principles of Cellular Proteostasis

• Subject Area: Biology ; Chemistry
• Term: from 2012 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 189682160

Proteostasis comprises multiple highly conserved and interconnected cellular processes that control the activity of individual proteins in space and time to ensure the functionality of the proteome, its continuous renewal, and its adaptation to environmental changes. At the posttranscriptional level, three main aspects of proteostasis can be defined: Protein biogenesis including translation, folding, transport, and assembly processes; Modulation of protein function, concentration, and localization by posttranslational modification; Protein quality control to recycle or remove misfolded or aggregated proteins to avoid accumulation of toxic products inside the cell. It is known that proteostasis naturally declines during aging or can reach its limits by extreme challenges. The profound consequence of a decline of cellular proteostasis for the entire organism is highlighted by the fact that many human diseases including cancer and neurodegenerative disorders are caused by misregulation of protein activities.To dissect the principles underlying proteostasis, the Collaborative Research Center (CRC) 969 combines, in a highly interdisciplinary and synergistic research approach, the expertise of Chemistry and Biology in order to:(i) understand the regulation of individual protein activities that act at cellular hubs of proteostasis, e.g. in protein folding and assembly, posttranslational modification, and protein degradation. (ii) study processes and mechanisms required to adapt the proteome to specific demands such as metabolic changes, cell division, viral infection, and stress.(iii) develop novel chemical tools and biophysical strategies to simulate, monitor or manipulate protein activities and thereby proteostasis in vitro and in vivo. Research in the CRC 969 carried out in 19 projects centers around three research areas reflecting the life cycle of proteins and thus the key pathways of proteostasis: (A) Protein Biogenesis, (B) Protein Modification, and (C) Protein Aggregation and Degradation.

• DFG Programme: Collaborative Research Centres

Completed projects

• A01 - Role of ribosome-associated Hsp70/Hsp40 chaperones in proteostasis (Project Head Deuerling, Elke )
• A02 - Protein structure formation studied by time-resolved infrared spectroscopy (Project Head Hauser, Karin )
• A03 - Biogenesis of ß-barrel proteins from Thermus thermophilus: Structure and mechanism (Project Heads Diederichs, Kay ;  Welte, Wolfram )
• A04 - Biogenesis and integration of metabolite translocators into membranes surrounding complex plastids (Project Head Kroth, Peter )
• A05 - Engineering of designer switches for controlling protein expression in eukaryotic model organisms (Project Head Hartig, Jörg Steffen )
• A06 - Architecture and structural dynamics of core components of the translational assembly scaffold (Project Head Stengel, Florian )
• A07 - Protein biogenesis and transport to the endoplasmic reticulum during health, aging and proteotoxic stress in Caenorhabditis elegans (Project Heads Deuerling, Elke ;  Gamerdinger, Ph.D., Martin )
• B01 - Regulation of the ubiquitin-ligase complex APC/C by XErp1 (Project Head Mayer, Thomas )
• B02 - Deregulation of protein ubiquitylation by human papillomavirus E6 oncoproteins (Project Head Scheffner, Martin )
• B03 - Unnatural amino acids to study protein ubiquitylation (Project Heads Marx, Andreas ;  Scheffner, Martin )
• B04 - Functional regulation of proteins by poly(ADP-ribose) (Project Heads Bürkle, Alexander ;  May, Elisa )
• B05 - Metabolic engineering of glycoproteins (Project Head Wittmann, Valentin )
• B06 - Protein complex assembly at focal adhesion sites (Project Head Hauck, Christof Robert )
• B07 - Regulation of the activity and localization of the motorprotein Kif18A by posttranslational modifications (Project Head Mayer, Thomas )
• B08 - Nucleotide-based activity probes: Dye-labeled ATP-analogues (Project Heads Marx, Andreas ;  Zumbusch, Andreas )
• B09 - Multiscale simulations and NMR spectroscopy of ubiquitin chains: linkage chemistry and chain behavior (Project Heads Kovermann, Michael ;  Peter, Christine )
• B10 - Visualizing ubiquitin processing in cells (Project Heads Marx, Andreas ;  Scheffner, Martin ;  Zumbusch, Andreas )
• C01 - The substrates of FAT10ylation and their proteolytic targeting (Project Heads Groettrup, Marcus ;  Isono, Erika )
• C02 - Protein quality control by DEG/HtrA proteases in the plant nucleus (Project Heads Adamska, Iwona ;  Funck, Dietmar )
• C03 - Investigating structure and dynamics of intrinsically disordered proteins by spin-label EPR (Project Head Drescher, Malte )
• C04 - Lipid binding of posttranslationally-modified alpha-synuclein as modulator of mitophagy and altered mitochondrial dynamics (Project Head Leist, Marcel )
• C05 - Local and transient structural features of the intrinsically disordered protein alpha-synuclein (Project Heads Drescher, Malte ;  Leist, Marcel ;  Peter, Christine )
• C06 - Bacterial metabolites influencing cross-species proteostasis (Project Head Böttcher, Thomas )
• C07 - Molecular determinants of the catalytic and scaffolding functions of the E3 ubiquitin ligase MuRF1 in the muscle sarcomere (Project Heads Diederichs, Kay ;  Mayans, Olga )
• C08 - Elucidation of the molecular mechanisms regulating the deubiquitylase AMSH and its targets (Project Head Isono, Erika )
• C09 - The structural and functional consequences of FAT10 phosphorylation (Project Heads Groettrup, Marcus ;  Mathies, Guinevere ;  Peter, Christine )
• C10 - Clearance of protein aggregates by exophers (Project Heads Annamalai, Karthikeyan ;  Gamerdinger, Ph.D., Martin )
• MGK - Integrated Research Training Group Proteostasis (Project Head Marx, Andreas )
• Z - Central Tasks (Project Head Deuerling, Elke )

• Applicant Institution: Universität Konstanz
• Spokesperson: Professorin Dr. Elke Deuerling