Who is BENDER?
BiogENesis and Degradation of ER proteins (BENDER) is a project funded by the European Union. The European Research Council (ERC) awarded a Consolidator Grant to prof. Friedrich Förster.
Eukaryotic cells have specific lipid-enclosed microenvironments, ‘organelles’, that provide suitable environments for particular biochemical reactions. The Endoplasmic Reticulum (ER) is the site, where a major portion of protein synthesis occurs. Approximately one third of the human genome is part of the secretory pathway: they are synthesized at the ER membrane, mature further in the ER and are transported to their eventual destination, such as the exterior of the cell (e.g., blood plasma for antibodies), the plasma membrane or intracellular organelles. The ER is equipped with an intricate protein network to govern the biogenesis and homeostasis of this large and diverse group of secretory pathway proteins. The molecular mechanisms of how this ER-residing machinery facilitate protein biogenesis and degradation are largely unknown to date. This is due to the molecular complexity and sophisticated regulation of this machinery in a secluded compartment, which is difficult to address by conventional structural biology approaches that address single isolated enzymes rather than large networks in their native environment. In this project, we use an integrative approach with cryo-electron tomography in its core to study the BiogENesis and Degradation of ER proteins (BENDER).
Due to the large amounts of proteins that are subject to the secretory pathway, the BENDER project is of great importance to fundamental science. Nevertheless, the significance of BENDER to society is beyond the pure gain of fundamental knowledge on the biochemistry that enables life. The ER homeostasis, in particular its adaptation to stress (unfolded protein response, UPR, and ER assicated degradation, ERAD) are implicated in more than 100 disorders ranging from cystic fibrosis, liver disease, epilepsy, cardiac arrhythmias, blindness, diabetes, and Alzheimer’s and Parkinson’s disease. While we do not specifically address any of these diseases within this proposal key concepts evolving from our studies will have implications on the mechanistic models underlying these chronic diseases and possible molecular targets addressing them. In this proposal we do directly address another biomedical aspect of proteins biogenesis in the ER: a number of viruses such as human cytomegalovirus evade the human immune system through targeting the biogenesis of a key defense molecule, Major Histocompatibility Complex I. The result will also impact our views on immunoevasion by many other viruses.
The overall goal of the BENDER project is to study the molecular architecture of the ER biogenesis and degradation machinery ‘in action’. Firstly, we focus on the static structure of the entry to the ER and secretory pathway, the ER translocon complex. This ‘swiss army knife’ can team up with specific cofactors, depending on the requirements of its various substrates and the state of the cell. We then study the ER translocon complex when it works on specific proteins. Furthermore, we focus on how the ER can maintain its homeostasis using degradation of proteins from the ER and by the unfolded protein response. Finally, we develop advanced computational methods for cryo-electron tomography that allow to most effectively distinguish different types of molecules involved in protein biogenesis and degradation as well as their different conformational states.