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TRR 83:  Molecular Architecture and Cellular Functions of Lipid/Protein Assemblies

Subject Area Biology
Medicine
Term from 2010 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 112927078
 
Final Report Year 2023

Final Report Abstract

The goal of the Transregional Collaborative Research Centre 83 was to characterize protein/lipid assemblies to reveal how the wide diversity of lipid species found in biological membranes determines cellular functions and structures, and to understand the underlying biophysical and chemical properties. The TRR 83 developed a toolbox of well over 100 functionalized lipid species that enabled the identification of novel lipid interaction partners, and spatial and temporal photoactivation allowed downstream signaling events to be monitored. Proteins interacting with cholesterol, distinct sphingolipids, phosphoinositides, and diacylglycerols were identified, allowing the identification of novel properties, for example in a lipid transfer system. The lipidomics platforms combined with high resolution imaging techniques (e.g CLEM) revealed the composition of largescale protein/lipid assemblies such as the hepatitis C virus (HCV) replication sites, HIV budding sites, and primary cilia. Reconstitution of purified proteins into lipid bilayers showed how transport vesicles are tethered to and fuse with their target membranes, how the fibroblast growth factor 2 forms transient pores and translocates across the plasma membrane and how cortical actomyosin polymerization can affect the compartmentalization of proteins in the membrane. Structural studies assigned unanticipated functions to lipids during the insertion of newly synthesized proteins into the endoplasmic reticulum (ER). In addition, they revealed how distinct lipids modulate the activity of epidermal growth factor receptor and how ligand binding induces conformational changes in the reconstituted insulin receptor. Super-resolution imaging showed that the functional assembly of tight junctions requires multivalent phase separation properties. Molecular mechanism linking Hedgehog signaling, involved in proper cell differentiation during embryogenesis, to cellular metabolism via endocannabinoids were discovered. Biophysical studies showed that cholesterol and calcium regulate the accessibility of phosphoinositides headgroups for protein interactions. In addition to mechanistic and structural insights, the TRR 83 research was also of medical importance. The discovery that cholesterol crystals activate the complement system and inflammasomes lead to novel therapeutic strategies. Clinical trials are testing whether an individual’s ability to dissolve cholesterol crystals is related to inflammation during atherogenesis. Biogenesis of HCV replication sites could be blocked by the clinically used NS5A inhibitor daclatasvir and the cyclophilin inhibitor cyclosporine D, revealing a new paradigm in antiviral therapy. Overall, members of the TRR 83 have established paradigms for protein-lipid interactions in several sub-cellular compartments and the chemical tools developed by the TRR 83 are being used by the world-wide membrane community. Strong technology platforms, complementary research expertise, model systems ranging from atomistic structures to entire organisms, and intensive scientific exchange characterized the research efforts of TRR 83.

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